Indole derivatives useful as endothelin receptor antagonists

ABSTRACT

##STR1## Compounds of formula (I), and their pharmaceutically acceptable derivatives, wherein R 1  and R 2  are optional substituents and independently represent C 1-6  alkyl, C 2-6  alkenyl optionally substituted by CO 2  H or CO 2  (C 1-6  alkyl, C 2-6  alkynyl, halogen, C 1-3  perfluoroalkyl, (CH 2 ) m  Ar 1 , (CH 2 ) m  Het 1 , (CH 2 ) m  CONR 7  R 8 , (CH 2 ) m  CO 2  R 8 , O(CH 2 ) q  CO 2  R 8 , (CH 2 ) m  COR 8 , (CH 2 ) m  OR 8 , O(CH 2 ) p  OR 8 , (CH 2 ) m  NR 7  R 8 , CO 2  (CH 2 ) q  NR 7  R 8 , (CH 2 ) m  CN, S(O) n  R 8 , SO 2  NR 7  R 8 , CONH(CH 2 ) m  Ar 1  or CONH(CH 2 ) m  Het 1  ; R 3  represents H, C 1-6  alkyl, (CH 2 ) p  CONR 9  R 10 , SO 2  R 10 , SO 2  NR 9  R 10 , (CH 2 ) m  COR 10 , C 2-6  alkenyl, C 2-6  alkynyl, (CH 2 ) m  CONR 9  R 10 , (CH 2 ) m  CO 2  R 10 , (CH 2 ) p  CN, (CH 2 ) p  R 10  or (CH 2 ) p  OR 10  ; R 4  represents H or C 1-6  alkyl; R 5  represents H or OH; R 6  represents phenyl optionally fused to a heterocylic ring, the group as a whole being optionally substituted; R 7-10  are fully defined herein and may independently represent Ar 2  or Het 2  ; Z represents CO 2  H, CONH(tetrazol-5-yl), CONHSO 2  O(C 1-4  alkyl), CO 2  Ar 3 , CO 2  (C 1-6  alkyl), tetrazol-5-yl, CONHSO 2  Ar 3 , CONHSO 2  (CH 2 ) q  Ar 3  or CONHSO 2  (C 1-6  alkyl); Ar 1-3  independently represent phenyl, naphthyl, or an aromatic heterocycle, which groups are optionally fused and optionally substituted; and Het 1  and Het 2  independently represent a non-aromatic heterocycle which is optionally substituted; are useful in the treatment of restenosis, renal failure and pulmonary hypertension.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a divisional application of U.S. Ser. No. 09/147,096, filed onOct. 5, 1998, now U.S. Pat. No. 6,017,945 which is the National Stage ofInternational Application No. PCT/EP97/01882, filed internationally onApr. 11, 1997, which claims priority to GB 9609641.7, filed May 9, 1996.

This invention relates to indole derivatives useful in the treatment ofa variety of diseases including restenosis, renal failure and pulmonaryhypertension, and to pharmaceutical formulations containing suchcompounds.

International Patent Application WO 94/14434 discloses indolederivatives which are indicated as endothelin receptor antagonists.European Patent Application 617001 discloses a large number ofphenoxyphenylacetic acid derivatives which are also indicated asendothelin receptor antagonists.

Bergman et al. Tetrahedron, Vol 31, No. 17, 1975, pages 2063-2073,disclose a number of indole-3-acetic acids. Similar compounds aredisclosed by Rusinova et al. Khim Geterotiskl Soedin, 1974, (2), 211-213(see also Chemical Abstracts. Vol 81, No. 7 Aug. 19, 1974, abstract No.37455a), and Yarovenko et al. J Gen Chem USSR (English translation), Vol39, 1969, page 2039 (see also Beilstein Registry Number 431619). Thesecompounds are not indicated in any kind of therapy, and proviso (i)below relates to them.

Julian et al. J Chem Soc. Chemical Communications, No. 1, 1973, disclosean N-p-chlorobenzoylindole derivative as a by-product of aphoto-addition reaction. The compound is not indicated in any kind oftherapy, and proviso (ii) below relates to it.

Yamamoto et al. Japanese Patent No. 70 041 381 (see also ChemicalAbstracts, Vol 75, No. 3, 1971, abstract No. 20189v), disclose anN-p-chlorobenzoylindole derivative which is indicated as ananti-inflammatory. Proviso (iii) below relates to it.

According to the present invention, there is provided a compound offormula I. ##STR2## wherein R¹ and R² are optional substituents andindependently represent C₁₋₆ alkyl, C₂₋₆ alkenyl [optionally substitutedby CO₂ H or CO₂ (C₁₋₆ alkyl)]. C₂₋₆ alkynyl, halogen, C₁₋₃perfluoroalkyl, (CH₂)_(m) Ar¹, (CH₂)_(m) Het¹, (CH₂)_(m) CONR⁷ R⁸.(CH₂)_(m) CO₂ R⁸, O(CH₂)_(q) CO₂ R⁸, (CH₂)_(m) COR⁸, (CH₂)_(m) OR⁸,O(CH₂)_(p) OR⁸, (CH₂)_(m) NR⁷ R⁸, CO₂ (CH₂)_(q) NR⁷ R⁸, (CH₂)_(m) CN,S(O)_(n) R⁸, SO₂ NR⁷ R⁸, CONH(CH₂)_(m) Ar¹ or CONH(CH₂)_(m) Het¹ ;

R³ represents H, C₁₋₆ alkyl, (CH₂)_(p) NR⁹ R¹⁰, SO₂ R¹⁰, SO₂ NR⁹ R¹⁰,(CH₂)_(m) COR¹⁰, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(m) CONR⁹ R¹⁰,(CH₂)_(m) CO₂ R¹⁰, (CH₂)_(p) CN, (CH₂)_(p) R¹⁰ or (CH₂)_(p) OR₁₀ ;

R⁴ and R⁹ independently represent H or C₁₋₆ alkyl;

R⁷ represents H, C₁₋₆ alkyl or C₁₋₆ alkoxy;

R⁵ represents H or OH;

R⁶ represents phenyl optionally fused to a saturated or unsaturated 5-or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selectedfrom N, S and O, the group as a whole being optionally substituted byone or more groups selected from C₁₋₆ alkyl, C₁₋₆ alkoxy and halogen,and wherein any members of the heterocyclic ring which are S may besubstituted by one or two oxygen atoms;

R⁸ and R¹⁰ independently represent H, C₁₋₆ alkyl, Ar², Het² or C₁₋₆alkyl substituted by Ar² or Het².

Z represents CO₂ H, CONH(tetrazol-5-yl), CONHSO₂ O(C₁₋₄ alkyl), CO₂ Ar³,CO₂ (C₁₋₆ alkyl), tetrazol-5-yl, CONHSO₂ Ar³, CONHSO₂ (CH₂)_(q) Ar³ orCONHSO₂ (C₁₋₆ alkyl);

m represents 0, 1, 2 or 3;

n represents 0, 1 or 2;

p represents 2, 3 or 4;

q represents 1, 2 or 3;

Ar¹⁻³ independently represent phenyl, naphthyl, or an aromaticheterocycle having 5 or 6 ring members up to 4 of which are selectedfrom N, S and O, which aromatic heterocycle is optionally fused to abenzene ring, and which phenyl group is optionally fused to an aromaticheterocycle as defined immediately above, the group as a whole beingoptionally substituted by one or more groups falling within thedefinition of R¹ above; and

Het¹ and Het² independently represent a non-aromatic heterocycle having5 or 6 ring members up to 4 of which are selected from N, S and O, whichgroup is optionally substituted by one or more groups falling within thedefinition of R¹ above, and is further optionally substituted by ═O or═S; provided that:

(i) when R¹ represents methoxy or is absent, R² is absent, R³ representsH, R⁴ represents H, methyl or ethyl, and R⁶ represents unsubstitutedphenyl, then Z does not represent CO₂ H or CO₂ (C₁₋₆ alkyl);

(ii) when R¹ and R² are absent, R³ represents CO(p--ClC₆ H₄), R⁴represents H, and R⁶ represents unsubstituted phenyl, then Z does notrepresent CO₂ (₁₋₆ alkyl); and

(iii) when R¹ represents methoxy, R² is absent, R³ represents CO(p--ClC₆H₄), R⁴ represents methyl, and R⁶ represents unsubstituted phenyl, thenZ does not represent CO₂ H;

or a pharmaceutically acceptable derivative thereof.

Pharmaceutically acceptable derivatives include those compounds in whichthe functional groups explicitly recited above have been derivatised toprovide prodrugs which can be converted to the parent compound in vivo.Such prodrugs are discussed in Drugs of Today, Vol 19, 499-538 (1983)and Annual Reports in Medicinal Chemistry, Vol 10, Ch 31 p306-326. Inaddition, pharmaceutically acceptable derivatives includepharmaceutically acceptable salts, such as alkali metal salts (forexample sodium salts) of any acidic groups that may be present.

"Halogen" includes fluorine, chlorine, bromine and iodine.

Alkyl groups which R¹⁻⁴, R⁶⁻¹⁰ and Z represent or comprise may bestraight chain, branched or cyclic.

Besides phenyl and naphthyl, specific groups that Ar¹⁻³ may represent orcomprise include indolyl, pyridinyl, thienyl, oxazolyl, thiazolyl,isothiazolyl, pyrazolyl, trizolyl, tetrazolyl, oxadiazolyl,thiadiazolyl, imidazolyl, thiazolinidyl, isoxazolyl, oxadiazolyl,thiadiazolyl, pyrrolyl and pyrimidinyl.

Specific groups that Het¹ and Het² may represent or comprise includeoxazolidinyl, trizolethione, triazolone, oxadiazolone, oxadiazolethione,imidazolidinyl, morpholinyl, piperidinyl and piperazinyl.

Preferred groups of compounds which may be mentioned include those inwhich:

(a) R¹ represents halogen, (CH₂)_(m) CONR⁷ R⁸, (CH₂)_(m) CO₂ R⁸,(CH₂)_(m) COR⁸, (CH₂)_(m) OR⁸ or (CH₂)_(m) CN. In these groups it ispreferred that R⁷ and R⁸ represent H or C₁₋₆ alkyl. Preferably, m is 0or 1. Thus, specific groups which may be mentioned are CONH₂, CO₂ H, CH₂OH, F or CH₃ CO. R¹ is preferably attached to the 6-position of theindole ring.

(b) R² is absent (i.e. its place on the indole ring is occupied by H).

(c) R³ represents H, C₁₋₆ alkyl or (CH₂)_(p) OR¹⁰. Preferably, R¹⁰ isC₁₋₆ alkyl and p is 2. Thus, specific groups which may be mentioned aremethyl and (CH₂)₂ OCH₃.

(d) R⁴ represents H.

(e) R⁵ represents H.

(f) R⁶ represents phenyl fused to a saturated 5-membered heterocyclicring, for example 3,4-methylenedioxyphenyl.

(g) Z represents CO₂ H or CONHSO₂ Ar³. Preferably, Ar³ is phenylsubstituted by one or more groups selected from C₁₋₆ alkyl, C₁₋₆ alkoxyand C₁₋₆ alkyl substituted by carboxy. Thus, specific groups which maybe mentioned are: ##STR3##

There is further provided a process for the production of the compoundsof the invention, comprising:

(a) when R⁵ represents H, reaction of a compound of formula IIA.##STR4## wherein R¹⁻⁴ are as defined above, with a compound of formulaIII. ##STR5## wherein R⁶ and Z are as defined above, in the presence ofa Lewis acid or trifluoroacetic acid, and a tri(C₁₋₆ alkyl)silane;

(b) when R⁵ represents OH, reaction of a compound of formula IIA, asdefined above, with a compound of formula III, as defined above, in thepresence of a Lewis acid;

(c) when R³ represents H and R⁵ represents H, treatment of a compound offormula IIB, ##STR6## wherein R¹, R² and R⁴ are as defined above, with aGrignard reagent, followed by reaction with a compound of formula III,as defined above, followed by treatment with a Lewis acid ortrifluoroacetic acid, and a tri(C₁₋₆ alkyl)silane;

(d) when R³ represents H and R³ represents H, treatment of a compound offormula IIB, as defined above, with a Grignard reagent, followed byreaction with a compound of formula IV, ##STR7## wherein R⁶ Z are asdefined above, and Hal represents halogen; (e) when R⁵ represents H,reaction of a compound of formula IIA, as defined above, with a compoundof formula IV, as defined above, in the presence of a hindered,non-nucleophilic base;

(f) reacting a compound of formula I, in which R¹ represents Br, with COgas in the presence of a palladium catalyst and a reducing agent, toprovide the corresponding compound of formula I in which R¹ representsCHO;

(g) reacting a compound of formula I, in which R¹ represents Br, with COgas in the presence of a palladium catalyst and a C₁₋₆ alkanol, toprovide the corresponding compound of formula I in which R¹ representsCO₂ (C₁₋₆ alkyl);

(h) coupling a compound of formula I in which Z represents CO₂ H with acompound of formula VI. wherein Ar³ is as defined above, to provide thecorresponding compound of formula I in which Z represents CONHSO₂ Ar³ ;or

(i) reacting a compound of formula I, in which R¹ represents Br, with analkyl lithium reagent and quenching with dimethylformamide or carbondioxide, to give a corresponding compound in which R¹ represents CHO orCO₂ H respectively;

and where desired or necessary converting the resulting compound offormula I into a pharmaceutically acceptable derivative thereof or viceversa.

In process (a), suitable Lewis acids include boron trifluoridediethyletherate. The reaction is preferably carried out in a solventwhich does not adversely affect the reaction, for exampledichloromethane, at a temperature below room temperature, for example-40 to -78° C. A preferred tri(C₁₋₆ alkyl)silane is triethylsilane.Intermediate compounds in which R⁵ represents OH may be isolated fromthis process.

In process (b), suitable Lewis acids include boron trifluoridediethyletherate. The reaction is preferably carried out in a solventwhich does not adversely affect the reaction, for exampledichloromethane, at a temperature below room temperature, for example-40 to -78° C. The reaction is followed by basic work up.

In process (c), suitable Grignard reagents include methylmagnesiumiodide. The reaction is preferably carried out in a solvent which doesnot adversely affect the reaction, for example toluene, below roomtemperature, for example -70° C. Suitable Lewis acids include borontrifluoride diethyletherate. The acid treatment may be carried out in asolvent which does not adversely affect the reaction, for exampledichloromethane, at a temperature of 0° C. to room temperature. Apreferred tri(C₁₋₆ alkyl)silane is triethylsilane.

In process (d), suitable Grignard reagents include methylmagnesiumiodide. The reaction is preferably carried out in a solvent which doesnot adversely affect the reaction, for example toluene, at or aroundroom temperature. The reaction mixture may be worked up with a weak acidsuch as aqueous ammonium chloride. Hal is preferably Br.

In process (e), suitable hindered non-nucleophilic bases include2,6-dimethylpyridine. The reaction is preferably carried out in asolvent which does not adversely affect the reaction, for exampledimethylformamide, at an elevated temperature, for example 80° C.

In process (f), suitable palladium catalysts includedichlorobis(triphenylphosphine)-palladium(II). Suitable reducing agentsinclude sodium formate. The reaction is preferably carried out in asolvent which does not adversely affect the reaction, for exampledimethylformamide, at an elevated temperature, for example 110° C.

In process (g), suitable palladium catalysts includedichlorobis(triphenylphosephine)-palladium(II). The reaction ispreferably carried out in a solvent which does not adversely affect thereaction, for example dimethylformamide, at an elevated temperature, forexample the reflux temperature of the reaction mixture.

In process (h), the reaction may be facilitated by the use ofconventional coupling agents, for example N,N-carbonyl diimidazole. Whenusing this agent, the acid is first reacted with the agent (for examplein dichloromethane at the reflux temperature of the solvent), and thenthe product of this reaction is reacted with the amine (preferably inthe presence of a strong hindered amine base such as1.8-diazabicyclo[5.4.0]undec-7-ene, in a solvent such as dichloromethaneat the reflux temperature of the solvent). An alternative agent is1-(3-dimethylaminopropyl)-3-ethylcarbodiimide which reacts at roomtemperature.

In process (i), suitable alkyl lithium reagents include n-butyl lithium.The reaction is carried out by adding the alkyl lithium reagent to thecompound of formula I in a solvent such as tetrahydrofuran, at atemperature below room temperature (for example -40 to -78° C.), andstirring for about 2 hours. Dimethylformamide or solid carbon dioxide isthen added and the reaction mixture allowed to warm to room temperature.

Compounds of formulae IIA, IIB, III, IV and VI are either known or maybe prepared by conventional methods well known to those skilled in theart. For example, compounds of formulae IIA and IIB may be prepared bythe Fischer, Reissert and Madelung syntheses. In addition, InternationalPatent Application WO 94/14434 discloses a number of routes to 2-carboxyindole derivatives (see page 8 onwards which may be decarboxylatedreadily (using copper and quinoline) to give compounds of formulae IIAor IIB in which R⁴ is H, or reduced to give compounds of formulae IIA orIIB in which R⁴ is alkyl. Other methods for the preparation of indolesare described by Moyer et al. J Org Chem, 1986, 51, 5106-5110; Wender etal. Tetrahedron, 1983, 39 No. 22, 3767-3776; Uhle, J Am Chem Soc, 1949,71, 761; Uhle et al, J Am Chem Soc, 1960, 82, 1200; Nagasaka et al,Heterocycles, 1977, 8, 371; Bowman et al, J Chem Soc. Perkin Trans 1,1972, 1121; Bowman et al. J Chem Soc, Perkin Trans 1, 1972, 1926; andClark et al, Heterocycles, 1984, 22, 195.

Compounds of formula III in which R⁶ is an electron-rich group (forexample 1,3-benzodioxole) and Z is CO₂ CH₂ CH₃ may be prepared by aFriedel-Crafts acylation between a compound of formula R⁶ H and thecompound of formula ClCOCO₂ CH₂ CH₃. The reaction is preferably carriedout in the presence of a Lewis acid (for example AlCl₃), in a solventwhich does not adversely affect the reaction, for exampledichloromethane, below room temperature (for example 0° C.).

Compounds of formula III in which R⁶ is not an electron-rich group (forexample groups substituted by halogen or OH) and Z is CO₂ CH₃ may beprepared by reaction of a compound of formula R⁶ Li with a compound offormula CH₃ OCOCO₂ CH₃. The reaction may be carried out in a solventwhich does not adversely affect the reaction, for exampletetrahydrofuran, below room temperature (for example -40° C. to -78°C.).

Compounds of formula R⁶ Li may be prepared by reacting a compound offormula R⁶ Br and butyl lithium. The reaction may be carried out in asolvent which does not adversely affect the reaction, for exampletetrahydrofuran, below room temperature (for example -78° C.).

Compounds of formula IV may be prepared by halogenating thecorresponding alcohol with an agent such as hydrobromic acid. When Zrepresents CO₂ (C₁₋₆ alkyl), compounds of formula R⁶ CH(OH)Z may beprepared by reacting an aldehyde of formula R⁶ CHO with bromoform underbasic conditions, and treating the crude carboxylic acid intermediatewith a C₁₋₆ alkanol.

Compounds of formula I may be converted into other compounds of formulaI using known techniques. Processes (f)-(i) above are such conversionsof particular interest.

Compounds of formulae I, III or IV in which Z represents a carboxylicester may be converted into corresponding compounds in which Zrepresents other groups by conventional methods.

Compounds of formulae I, IIA or IIB in which R³ represents H may beconverted to corresponding compounds in which R³ is other than H byconventional methods. In general, R³ groups other than H may be added bytreatment of a compound of formula I, IIA or IIB in which R³ representsH with sodium hydride, followed by an appropriate compound of formula R³Br or R³ I, in dimethylformamide at 0° C. Preferably, compounds offormulae I, IIA or IIB in which R³ represents electron-withdrawinggroups (such as SO₂ R¹⁰, SO₂ NR⁹ R¹⁰, CONR⁹ R¹⁰ and COR¹⁰) are preparedby reacting a compound of formula I, IIA or IIB in which R³ represents Hwith an appropriate compound of formula R³ Cl.

The compounds of the invention may be separated and purified byconventional methods.

It will be apparent to those skilled in the art that sensitivefunctional groups may need to be protected and deprotected duringsynthesis of a compound of the invention. This may be achieved byconventional techniques, for example as described in `Protective Groupsin Organic Synthesis` by T W Greene and P G M Wuts, John Wiley and SonsInc. 1991. For example, it may be desirable to protect the indolenitrogen of a compound of formula IIA and use the method of process (a)followed by deprotection to give a compound of formula I in which R³represents H. Processes (a)-(h) embrace such protection and deprotectionsteps.

The synthesis of trizolethione, oxadiazolone and oxadiazolethione isdescribed in J Med Chem, 1993, 36, 1090-1099. The synthesis ofoxathiadiazole is described in Bioorganic and Medicinal ChemistryLetters, 1994, 4 No. 1, 41-44.

The compounds of the invention may possess one or more chiral centresand so exist in a number of stereoisomeric forms. All stereoisomers andmixtures thereof are included in the scope of the present invention.Racemic compounds may either be separated using preparative HPLC and acolumn with a chiral stationary phase or resolved to yield individualenantiomers utilising methods known to those skilled in the art. Inaddition, chiral intermediate compounds may be resolved and used toprepare chiral compounds of formula I.

The compounds of the invention are useful because they havepharmacological activity in animals, including humans. Moreparticularly, they are useful in the treatment of restenosis, renalfailure, pulmonary hypertension, benign prostatic hypertrophy,congestive heart failure, stroke, angina, atherosclerosis, cerebral andcardiac ischaemia and cyclosporin induced nephrotoxicity. The treatmentof restenosis, renal failure and pulmonary hypertension are ofparticular interest. The compounds of the invention may be administeredalone or as part of a combination therapy.

Thus, according to a further aspect of the invention, there is provideda compound of formula I, as defined above, but without provisos (i) and(ii), or a pharmaceutically acceptable derivative thereof, for use as apharmaceutical.

There is further provided a pharmaceutical formulation comprising acompound of formula I, as defined above, but without provisos (i) and(ii), or a pharmaceutically acceptable derivative thereof, and apharmaceutically acceptable adjuvant, diluent or carrier.

The invention also provides the use of a compound for formula I, asdefined above, but without provisos (i)-(iii), or a pharmaceuticallyacceptable derivative thereof, in the manufacture of a medicament forthe treatment of restenosis, renal failure, pulmonary hypertension,benign prostatic hypertrophy, congestive heart failure, stroke, angina,atherosclerosis, cerebral and cardiac ischaemia or cyclosporin inducednephrotoxicity. The invention also provides a method of treatment ofthese diseases, which comprises administering a therapeuticallyeffective amount of a compound of formula I, as defined above, butwithout provisos (i)-(iii), or a pharmaceutically acceptable derivativethereof, to a patient in need of such treatment.

Without being limited by theory, the compounds of the invention arebelieved to be endothelin receptor antagonists. Endothelin (ET) is apotent vasoconstrictor synthesised and released by endothelial cells.There are three distinct isoforms of ET: ET-1, ET-2 and ET-3, all being21-amino acid peptides and herein the term `endothelin` refers to any orall of the isoforms. Two receptor subtypes, ET_(A) and ET_(B) have beenpharmacologically defined (see for example H. Arai et al. Nature, 348,730, 1990) and further subtypes have recently been reported. Stimulationof ET_(A) promotes vasoconstriction and stimulation of ET_(B) receptorscauses either vasodilation or vasoconstriction.

The effects of endothelin are often long-lasting and, as the endothelinsare widely distributed in mammalian tissues, a wide range of biologicalresponses have been observed in both vascular and non-vascular tissue.The main effects of endothelin are observed in the cardiovascularsystem, particularly in the coronary, renal, cerebral and mesentericcirculation.

Increased circulating levels of endothelin have been observed inpatients who have undergone percutaneous transluminal coronaryangioplasty (PTCA) (A. Tahara et al. Metab. Clin. Exp. 40, 1235, 1991)and ET-1 has been found to induce neointimal formation in rats afterballoon angioplasty (S. Douglas et al. J. Cardiovasc. Pharm., 22 (Suppl8), 371, 1993). The same workers have found that an endothelinantagonist, SB-209670, causes a 50% reduction in neointimal formationrelative to control animals (S. Douglas et al. Circ Res, 75, 1994).Antagonists of the endothelin receptor may thus be useful in preventingrestenosis post PTCA.

Endothelin-1 is produced in the human prostate gland and endothelinreceptors have been identified in this tissue. Since endothelin is acontractile and proliferative agent endothelin antagonists could beuseful in the treatment of benign prostate hypertrophy.

There is widespread localisation of endothelin and its receptors in thecentral nervous system and cerebrovascular system (R. K. Nikolov et al.Drugs of Today, 28(5), 303, 1992) with ET being implicated in cerebralvasospasm, cerebral infarcts and neuronal death. Elevated levels ofendothelin have also been observed in patients with:

Chronic renal failure (F. Stockenhuber et al. Clin Sci (Lond.). 82, 255,1992)

Ischaemic Heart Disease (M. Yasuda, Am. Heart J. 119, 801, 1990)

Stable of unstable angina (J. T. Stewart, Br. Heart J. 66, 7 1991)

Pulmonary Hypertension (D. J. Stewart et al, Ann Internal Medicine, 114,464

Congestive heart failure (R. J. Rodeheffer et al. Am. J. Hypertension,49A, 1991)

Preeclampsia (B. A. Clark et al. Am. J. Obstet. Gynecol., 166, 962,1992)

Diabetes (A. Collier et al. Diabetes Care, 15 (8), 1038, 1992)

Crohn's disease (S. H. Murch et al. Lancet, 339, 381, 1992)

Atherosclerosis (A. Lerman et al. New Eng. J. Med., 325, 997, 1991)

In every case the disease state associated with the physiologicallyelevated levels of endothelin is potentially treatable with anendothelin receptor antagonist and hence a compound of the invention.

Compounds that selectively antagonise the ET_(A) receptor rather thanthe ET_(B) receptor are preferred.

The biological activity of the compounds of the invention may bedemonstrated in Tests A-C below:

A. Binding assay

Competition between test compounds and ¹²⁵ I-ET-1 binding to humanendothelin receptors is determined as follows.

Binding to ET_(A) receptors

25 μl of a 30 pM solution of [¹²⁵ I]Tyr¹³ ET-1 (specific activity 2,220Ci/mM) is mixed with 25 μl samples of test compound (finalconcentrations in the range 0.1 nM-50,000 nM). 200 μl of a solutioncontaining cloned human ET_(A) receptor (0.75 pmoles receptorprotein/ml). 50 mM Tris. 0.5 mM CaCl₂, 0.1% human serum albumen, 0.1%bacitracin, 0.05% Tween 20, pH 7.4 is added. The solution is mixed at37° C. for 2 hours. After the incubation, the unbound ligand isseparated from receptor bound ligand by filtration with a Brandel cellharvester, followed by three washes of buffer. Filter papers are countedfor radioactivity, and the IC₅₀ (the concentration of test compound atwhich 50% of the radio-labelled compound is unbound) determined for theconcentration range tested.

Binding to ET_(B) receptors

25 μl of a 30 pM solution of [¹²⁵ I]Tyr¹³ ET-1 (specific activity 2,220Ci/mM) is mixed with 25 μl samples of test compound (finalconcentrations in the range 0.1 nM-50,000 nM). 200 μl of a solutioncontaining cloned human ET_(B) receptor (0.25 pmoles receptorprotein/ml), 50 mM Tris. 0.5 mM CaCl₂, 0.1% human serum albumen, 0.1%bacitracin, 0.05% Tween 20, pH 7.4 is added. The solution is mixed at37° C. for 2 hours. After the incubation, the unbound ligand isseparated from receptor bound ligand by filtration with a Brandel cellharvester, followed by three washes of buffer. Filter papers are countedfor radio-activity, and the IC₅₀ (the concentration of test compound atwhich 50% of the radio-labelled compound is unbound) determined for theconcentration range tested.

B. In vitro vascular smooth muscle activity

Rat aorta

Rat aortae are cleaned of connective tissue and fat and cut into helicalstrips approx 4 mm in width. The endothelium is removed by dragging theluminal surface of the tissue gently across filter paper moistened withKrebs solution of composition (mM) NaCl 130, KCl 5.6, NaHCO₃ 25, Glucose11.1, NaH₂ PO₄ 0.6, CaCl₂ 2.16, MgCl₂ 0.5, gassed with 95% O₂ /5% CO₂.The strips are mounted in isolated organ baths in Krebs solution under aresting tension of 1 gram. Organ bath solutions are maintained at 37° C.and continuously aerated with 95% O₂ /5% CO₂. Tensions are measured withMaywood Industries isometric force transducers and displayed on GouldTA4000 recorders. After equilibration in the organ bath for 1 hour,tissues are contracted by the addition of KCl to a final concentrationof 60 mM. The KCl is removed by replacing the Krebs solution, with twofurther washes with Krebs solution. To determine the potency of anET_(A) receptor antagonist, two tissues are cumulatively dosed with ET-1(0.1 nM-1 μM): other tissues are dosed with ET-1 (0.1 nM-1 μM) induplicate, beginning 30 minutes after the inclusion in the organ bathmedium of the test compound. Sufficient tissues are used per experimentto generate dose-response curves to ET-1 in the absence and the presenceof at least 3 concentrations of antagonist. Data are expressed as themean=s.e.m. Dissociation constants (k_(b)) of competitive antagonistsare calculated by the method of Arunlakshana and Schild.

Rabbit pulmonary artery

Isolated rabbit pulmonary arteries are cleaned of connective tissue andfat and cut into rings approx 4 mm in width. The endothelium is removedby inserting a fibrous instrument moistened with Krebs solution ofcomposition (mM) NaCl 130, KCl 5.6, NaHCO₃ 25, Glucose 11.1, NaH₂ PO₄0.6 CaCl₂ 2.16, MgCl₂ 0.5, gassed with 95% O₂ /5% CO₂. The rings aremounted in isolated organ baths in Krebs solution under a restingtension of 1 gram. Organ bath solutions are maintained at 37° C. andcontinuously aerated with 95% O₂ /5% CO₂. Tensions are measured withMaywood Industries isometric force transducers and displayed on GouldTA4000 recorders. After equilibration in organ bath for 1 hour, tissuesare contracted by the addition of KCl to a final concentration of 60 mM.The KCl is removed by replacing the Krebs solution, with two furtherwashes with Krebs solution. To determine the potency of an ET_(B)receptor antagonist, two tissues are cumulatively treated with BQ-3020(0.1 nM-1 μM): other tissues are treated with BQ-3020 (0.1 nM-1 μM) induplicate, beginning 30 minutes after the inclusion in the organ bathmedium of the test compound. Sufficient tissues are used per experimentto generate dose-response curves to BQ-3020 in the absence and thepresence of at least 3 concentrations of antagonist. Data are expressedas the mean=s.e.m. Dissociation constants (k_(b)) of competitiveantagonists are calculated by the method of Arunlakshana and Schild.

C. In vivo blockade of endothelin-induced blood pressure elevation

In anaesthetised, ganglion-blocked and artificially respired rats, theleft common carotid artery and the right jugular vein are cannulated forthe measurement of arterial blood pressure and the administration ofcompound respectively. Rats are treated with the ET_(B) antagnoistBQ-788 (0.25 mg/kg i.v.). Beginning 10 minutes after administeringBQ-788, the hypertensive response to ET-1 (1 μg/kg i.v.) is determined.When the blood pressure has returned to baseline, the test compound isadministered (0.1-20 mg/kg i.v.) and after 10 minutes the ET-1 challengeis repeated. Increasing concentrations of the test compound areadministered, followed 10 minutes after each administration by a furtherET-1 challenge. An IC₅₀ is determined based upon inhibition of ET-1induced pressor response upon cumulative dosing with compound.

Duration of blockade is determined in anaesthetised, ganglion-blockedand artificially respired rats, in which the left common carotid arteryand the right jugular vein are cannulated for the measurement ofarterial blood pressure and the administration of compound respectively.Rats are treated with the ET_(B) antagonist BQ-788 (0.25 mg/kg i.v.).Beginning 10 minutes after administering BQ-788, the hypertensiveresponse to ET-1 (1 μg/kg i.v.) is determined. When the blood pressurehas returned to baseline, the test compound is administered (10 mg/kgi.v.). Further administrations of ET-1 are made 5, 20 or 60 minutesafter dosing the test compound. In separate animals, prepared similarly,an ET-1 challenge is made 2 or 4 hours after dosing with the testcompound, in these animals BQ-788 is dosed 10 minutes before the ET-1challenge. For later time points, rats are dosed with the test compound(10 mg/kg) i.v. via a tail vein or p.o., they are then anaesthetised andprepared for blood pressure measurement as above. In these rats, ET-1 (1μg/kg i.v.) was administered 6 or 8 hours after the test compound.

For human use the compounds of the invention can be administered alonebut will generally be administered in admixture with a pharmaceuticalcarrier selected with regard to the intended route of administration andstandard pharmaceutical practice. For example they can be administeredorally in the form of tablets containing such excipients as starch orlactose or in capsules or ovules either alone or i admixture withexcipients or in the form of elixirs, solutions or suspensionscontaining the compound or salt in a liquid carrier, for example avegetable oil, glycerine or water with a flavouring or colouring agent.They can be injected parenterally, for example intravenously,intramuscularly or subcutaneously. For parental administration, they arebest used as sterile aqueous solutions which may contain othersubstances, for example, enough glucose or salts to make the solutionisotonic with blood. For parenteral administration the compound or saltmay also be administered as a solution or suspension in a suitable oil,for example polyethylene glycol, lecithin or sesame oil.

Compounds of the invention may also be administered through inhalationof a solution, suspension or emulsion that may be administered as a drypowder or in the form of an aerosol using a conventional propellant suchas dichlorodifluoromethane.

For oral or parenteral administration to human patients the daily dosagelevels of compounds of the invention will be from 0.01 to 30 mg/kg (insingle or divided doses) and preferably will be in the range 0.01 to 5mg/kg: Thus tablets will contain 1 mg to 0.4 g of compound foradministration singly or two or more at a time, as appropriate. Theabove dosages are, of course only exemplary of the average case andthere may be instances where higher or lower doses are merited, and suchare within the scope of the invention.

Alternatively the compounds of the invention can be administered in theform of a suppository or pessary, or they may be applied topically inthe form of a lotion, solution, cream, ointment or dusting powder or inthe form of a medicated plaster, patch or membrane. For example they maybe incorporated in a cream containing an aqueous emulsion ofpolyethylene glycols or liquid paraffin. The compounds may also beadministered intranasally.

The invention is illustrated by the following Examples, in which thefollowing abbreviations are used:

    ______________________________________                                        APCI        atmospheric pressure chemical ionisation                            DMF dimethylformamide                                                         DMSO dimethylsulphoxide                                                       Et ethyl                                                                      h hour                                                                        iPr isopropyl                                                                 LRMS low resolution mass spectroscopy                                         min minute                                                                    Me methyl                                                                     NMR nuclear magnetic resonance                                                TFA trifluoroacetic acid                                                      Tlc thin layer chromatography                                               ______________________________________                                    

EXAMPLE 1 Ethyl2-[3-(1-ethyl-6-methoxycarbonyl)indoyl]-2-(3,4-methylenedioxyphenyl)acetat

(a) 6-Bromo-1-ethylindole ##STR8##

Sodium hydride (480 mg of a 60% dispersion in mineral oil) was added toa stirred solution of 6-bromoindole (1.8 g 9.2 mmol) indimethylformamide (20 ml) at 0° C. under a nitrogen atmosphere. After 1hour bromoethane (1.1 ml. 14.7 mmol) was added and the cooling bathremoved. After 12 hours the dimethylformamide was removed in vacuo. Theresidue was purified directly by flash column chromatography (using 95%hexane, 5% ethyl acetate as eluant) to give 2.1 g of the subtitlecompound as a yellow oil.

¹ H NMR (300 MHz. CDCl₃):δ=1.45 (t, 3H), 4.10 (q, 2H), 6.45 (d, 1H),7.10 (d, 1H), 7.20 (d, 1H), 7.45 (d, 1H), 7.55 (s, 1H)

LRMS (Thermospray: 224 (MH⁻)

(b) 6-Methoxycarbonyl-1-ethylindole ##STR9##

Sec-butyllithium (9.4 ml of a 1.3M solution in cyclohexane) was added toa stirred solution of 6-bromo-1-ethylindole [the compound of step (a),2.5 g] in diethylether (20 ml) at -78° C. under a nitrogen atmosphere.After 30 minutes this solution was transferred by cannula to a stirredsolution of methyl chloroformate (1.29 ml, 16.74 mmol) in diethyl ether(8 ml) at -78° C. under a nitrogen atmosphere. After 1 hour the coolingbath was removed and the mixture was allowed to warm to roomtemperature. After a further 1 hour the mixture was poured into brineand extracted with ethyl acetate. The organic layers were dried (MgSO₄)and concentrated in vacuo to give a yellow oil. Flash columnchromatography (elution with 90% hexane, 10% ethyl acetate) gave 1.76 gof the subtitle compound as a pale yellow oil.

¹ H NMR (300 MHz. CDCl₃):δ=1.50 (t, 3H), 4.00 (s, 3H), 4.25 (q, 2H),6.50 (d, 1H), 7.25 (d, 1H), 7.60 (d, 1H), 7.80 (d, 1H), 8.10 (s, 1H)

LRMS (Thermospray: 204.2 (MH⁺)

(c) Benzo(1,3)dioxol-5-yl-oxo-acetic acid ethyl ester ##STR10##

A mixture of ethyl oxalyl chloride (50 ml, 0.45 mmol) and1,3-benzodioxole (50 g, 0.41 mmol) in dichloromethane (40 ml) was addeddropwise to a stirred slurry of aluminium trichloride (71 g, 0.53 mmol)in dichloromethane (500 ml) at 0° C. under a nitrogen atmosphere. After2 hours the mixture was poured into iced water and the organic layer waswashed with further volumes of water (3×500 ml), saturated sodiumbicarbonate solution (500 ml) and brine (500 ml). The organic layer wasdried (magnesium sulphate) and concentrated to give an orange oil. Flashcolumn chromatography (90% hexane, 10% ethyl acetate) gave 30 g of thesubtitle compound as a pale yellow oil.

¹ H NMR (300 MHz. CDCl₃):δ=1.40 (t, 3H), 4.40 (q, 2H), 6.10 (s, 2H),6.85 (d, 1H), 7.50 (s, 1H), 7.60 (d, 1H).

LRMS (Thermospray: 240 (MNH₄ ⁻)

(d) Ethyl2-[3-(1-ethyl-6-methoxycarbonyl)indolyl]-2-(3,4-methylenedioxyphenyl)acetate##STR11##

A mixture of 6-methoxycarbonyl-1-ethylindole [the compound of step (b),2.1 g, 10.3 mmol] and benzo(1,3)dioxol-5-yl-oxo-acetic acid ethyl ester[the subtitle compound of step (c), 2.4 g, 10.9 mmol] in dichloromethane(10 ml) was added dropwise to a solution of triethylsilane (6.4 ml, 51.5mmol) and boron trifluoride diethyletherate (3.28 ml, 20.6 mmol) indichloromethane (15 ml) at -78° C. under a nitrogen atmosphere. After 1hour the deeply coloured mixture was warmed to -40° C. After 10 hoursthe mixture was warmed to room temperature and poured into sodiumhydroxide solution (200 ml) of 1M). The flask was washed withdichloromethane (150 ml) and the 2 phase were vigorously shaken. Theorganic layer was separated and washed with brine before drying (MgSO₄)and concentrating in vacuo. Flash column chromatography (elution with90% hexane, 10% ethyl acetate) gave 4.2 g of the title compound as aclear oil.

¹ H NMR (300 MHz. CDCl₃):δ=1.45 (t, 3H), 4.00 (s, 3H), 4.25 (q, 2H),5.15 (s, 1H), 5.90 (s, 2H), 6.70 (d, 1H), 6.80 (d, 1H), 6.85 (s, 1H),7.30 (s, 1H), 7.40 (d, 1H), 7.70 (d, 1H), 8.10 (s, 1H)

LRMS (Thermospray: 410.2 (MH⁻)

EXAMPLE 22-[3-(1-Ethyl-6-methoxycarbonyl)indolyl]-2-(3,4-methylenedioxyphenyl)aceticacid ##STR12##

Sodium hydroxide solution (5 ml of 2M) was added to a stirred solutionof ethyl2[3-(1-ethyl-6-methoxycarbonyl)indolyl]-2-(3,4-methylenedioxyphenyl)acetate[the title compound of Example 1, 3.76 g, 9.2 mmol] in a 2:1 mixture oftetrahydrofuran and methanol (30 ml) at room temperature. The mixturewas heated at reflux for 6 hours, following closely by tlc. beforerecooling and removing the organic solvents in vacuo. The residue waspoured into sodium hydroxide solution (200 ml of 0.5M) and extractedwith dichloromethane to recover any unreacted starting material. Theaqueous layer was then acidified to pH1 with 2M hydrochloric acid andextracted with dichloromethane (2×300 ml). The organic fractions werecombined, dried and concentrated in vacuo to give the crude product asan oil. Flash column chromatography (elution with 94% dichloromethane,5% methanol, 1% ammonia) gave the title compound as a clear oil.

¹ H NMR (300 MHz. CDCl₃):δ=1.45 (t, 3H), 3.95 (s, 3H), 4.20 (q, 2H),5.20 (s, 1H), 5.95 (s, 2H), 6.80 (d, 1H), 6.85 (d, 1H), 6.90 (s, 1H),7.35 (s, 1H), 7.40 (d, 1H), 7.85 (d, 1H), 8.10 (s, 1H)

LRMS (Thermospray: 382.6 (MH⁻)

EXAMPLE 3N-(4-Iso-propylbenzenesulphonyl)-2-[3-(1-ethyl-6-methoxycarbonyl)indolyl]-2-(3,4-methylenedioxyphenyl)acetamide##STR13##

N,N-Carbonyl diimidazole (0.99 g, 6.14 mmol) was added to a stirredsolution of2-[3-(1-ethyl-6-methoxycarbonyl)indolyl]-2-(3,4-methylenedioxyphenyl)aceticacid [the title compound of Example 2, 1.8 g 4.7 mmol] indichloromethane (60 ml) at room temperature under a nitrogen atmosphere.The solution was heated to reflux for 12 hours. The mixture was cooledand 1.8-diazabicyclo[5.4.0]undec-7-ene (0.92 ml, 6.14 mmol) and4-iso-propylbenzenesulphonamide (1.03 g, 5.17 mmol) were added. Themixture was refluxed for a further 12 hours. After cooling the mixturewas poured into ammonium chloride solution (200 ml) and extracted intodichloromethane. The organic fractions were dried (MgSO₄) andconcentrated to give a yellow oil. Flash column chromatography usingfirstly dichloromethane and then 3% methanol in dichloromethane gave1.95 g of the title compound as a pale yellow oil.

¹ H NMR (300 MHz. CDCl₃):δ=1.30 (d, 6H), 1.45 (t, 3H), 3.00 (m, 1H),3.95 (s, 3H), 4.20 (q, 2H), 5.00 (s, 1H), 5.90 (s, 2H), 6.60 (s, 1H),6.70 (d, 2H), 7.05 (s, 1H), 7.10 (d, 1H), 7.35 (d, 2H), 7.65 (d, 1H),7.80 (d, 2H), 8.10 (s, 1H), 8.20 (brs, 1H)

LRMS (Thermospray: 580.4 (MNH₄ ⁺)

EXAMPLE 4N-(4-Iso-propylbenzenesulphonyl)-2-[3-(1-ethyl-6-carboxy)indolyl]-2-(3,4-methylene-dioxyphenyl)acetamide##STR14##

Aqueous KOH (14.2 ml of a 1M solution) was added to a stirred solutionofN-(4-iso-propylbenzenesulphonyl)-2-[3-(1-ethyl-6-methoxycarbonyl)indolyl]-2-(3,4-methylenedioxyphenyl)acetamide[the title compound of Example 3, 2 g, 3.56 mmol] in methanol (50 ml)and the solution was heated at reflux for 8 hours. After cooling themethanol was removed in vacuo and the resulting solution was partitionedbetween 1M hydrochloric acid (100 ml) and dichloromethane (3×100 ml).The organic fractions were dried (MgSO₄) and concentrated to give ayellow solid. Flash column chromatography (using 95% dichloromethane/5%methanol as eluant) gave the title compound as a white solid.

¹ H NMR (300 MHz. CDCl₃):δ=1.25 (d, 6H), 1.40 (t, 3H), 3.00 (m, 1H),4.15 (q, 2H), 5.00 (s, 1H), 5.90 (s, 2H), 6.65 (d, 2H), 6.70 (s, 1H),7.00 (s, 1H), 7.15 (m, 1H), 7.30 (d, 2H), 7.60 (m, 1H), 7.85 (d, 2H),8.10 (s, 1H)

LRMS (Thermospray: 566.3 (MNH₄ ⁺)

Analysis: Found C, 63.29: H, 5.21: N, 4.95 C₂₉ H₂₈ N₂ O₇ S requires: C,63.49; H, 5.14; N, 5.11.

EXAMPLE 5N-(4-Iso-propylbenzenesulphonyl)-2-[3-(1-ethyl-6-methylamido)indoyl]-2-(3,4-methylenedioxyphenyl)acetamide##STR15##

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg,0.294 mmol) was added to a stirred solution ofN-(4-iso-propylbenzenesulphonyl)-2-[3-(1-ethyl-6-carboxy)indolyl]-2-(3,4-methylenedioxyphenyl)acetamide(the title compound of Example 4, 124 mg. 0.23 mmol),hydroxybenzotrizole (37 mg. 0.27 mmol), triethylamine (63 μl. 0.45 mmol)and methylamine hydrochloride (23 mg. 0.34 mmol) in dichloromethane (7ml) at room temperature under a nitrogen atmosphere. After 12 hours thereaction mixture was poured into aqueous sodium hydrogen carbonatesolution and extracted with dichloromethane (3×100 ml). The combinedorganic fractions were dried (MgSO₄) and concentrated to give a yellowsolid. Flash column chromatography (using ethyl acetate as eluant) gavethe title compound as a yellow solid.

¹ H NMR (300 MHz. CDCl₃):δ=1.25 (d, 6H), 1.40 (t, 3H), 3.00 (m, 1H),3.05 (d, 3H), 4.05 (q, 2H), 5.00 (s, 1H), 5.90 (s, 2H), 6.30 (d, 1H),6.65 (d, 1H), 6.70 (s, 1H), 6.90 (d, 1H), 6.95 (s, 1H), 7.10 (d, 1H),7.25 (s, 1H), 7.30 (d, 2H), 7.85 (d, 2H), 7.90 (s, 1H), 9.40 (brs, 1H).

LRMS (Thermospray: 562 (MH⁺)

Examples 6-10 were prepared by the method of Example 6, using theproduct of Example 4 and the appropriate substituted amine startingmaterials. Their physical data are shown in Table-1.

                                      TABLE 1                                     __________________________________________________________________________      #STR16##                                                                       -                                                                            Example  N.sup.0                                                                              Physical Data                                               __________________________________________________________________________      6                                                                                             #STR18##                                                                    .sup.1 H NMR (300 MHz, CDCl.sub.3): δ = 1.25 (d,                        6H), 135 (t,  3H), 2.30 (s, 3H), 2.40 (m, 4H), 2.95 (m,                       1H), 3.50 (m,  2H), 4.00 (m, 2H), 4.20 (q, 2H), 5.00 (s,                      1H), 5.95 (s,  2H).   2H), 6.65 (d, 2H), 6.70 (s, 1H),                        6.85 (d, 1H), 7.00 (m,  1H), 7.20 (m, 3H), 7.40 (s, 1H),                      7.80 (d, 2H),  LRMS (Thermospray); 631.5 (MH.sup.-)                             - 7                                                                           .sup.1 H NMR (300 MHz, CDCl.sub.3): δ = 1.25                          (d,6H), 1.40 (t,  3H), 3.00 (m, 1H), 3.70 (m, 8H), 4.10                       (q, 2H), 4.90 (s,  1H), 5.90 (s, 2H), 6.60 (s, 1H), 6.70                      (m, 2H), 6.95 (m,  3H), 7.30 (d, 2H), 7.40 (s, 1H), 7.80                      (d, 2H), 8.85 (brs,  1H)  LRMS (Thermospray): 618                             (MH.sup.+)                                                       - 8                                                                                          .sup.1 H NMR (300 MHz, CD.sub.3 OD): δ = 1.25 (d,                     6H), 1.40 (t,  3H), 3.00 (m, 1H), 4.20 (q, 2H), 5.10 (s,                      1H), 5.80 (s,  2H), 6.70 (d, 2H), 6.75 (s, 1H), 7.00 (s,                      1H), 7.15 (m,  1H), 7.30 (d, 1H), 7.40 (d, 2H), 7.50 (d,                      1H), 7.75 (m,  1H), 7.80 (d, 2H), 8.05 (s, 1H), 8.20 (d,                      1H), 8.35 (m,  1H)  LRMS (Thermospray): m/z = 625.3                           (MH.sup.+)                                                       - 9                                                                                          .sup.1 H NMR (300 MHz, CD.sub.3 OD): δ = 1.25 (d,                     6H), 1.40 (t,  3H), 3.00 (m, 1H), 3.30 (s, 6H), 4.20 (q,                      2H), 5.10 (s,  1H), 5.95 (s, 2H), 6.60 (s, 1H), 6.65 (s,                      2H), 6.90 (s,  1H), 6.95 (d, 1H), 7.20 (d, 1H), 7.40 (d,                      2H), 7.45 (s,  1H), 7.80 (d, 2H)  LRMS (Thermospray):                         576.6 (MH.sup.+)                                                 - 10                                                                                         .sup.1 H NMR (300 MHz, CDCl.sub.3): δ = 1.25 (d,                      6H), 1.40 (t,  3H), 3.00 (m, 1H), 3.40 (s, 3H), 3.60 (s,                      3H), 4.10 (q,  2H), 5.00 (s, 1H), 5.90 (s, 2H), 6.65 (d,                      2H), 6.70 (s,  1H), 7.00 (s, 1H), 7.25 (m, 2H), 7.30 (d,                      2H), 7.75 (s,  1H), 7.80 (d, 2H)  LRMS (Thermospray):                         609.5 (MNH.sub.4.sup.-)                                       __________________________________________________________________________

EXAMPLE 11N-(4-Iso-propylbenzenesulphonyl)-2-[3-11-ethyl-6-(1,3,4-oxadiazol-2(3H)-one)lindolyl]-2-(3,4-methylenedioxyphenyl)acetamide##STR23##

Oxalyl chloride (0.065 ml. 0.74 mmol) was added to a stirred solution ofN-(4-iso-propylbenzenesulphonyl)-2-[3-(1-ethyl-6-carboxy)indolyl]-2-(3,4-methylenedioxyphenyl)-acetamide(the compound of Example 4, 340 mg, 0.62 mmol) in dry tetrahydrofuran(10 ml) at room temperature under a nitrogen atmosphere.Dimethylformamide (3 drops) was added and stirring was continued at roomtemperature for 2 hours. The solvent was removed in vacuo (azeotropingtwice with toluene) and the residue redissolved in tetrahydrofuran (5ml). This solution was added to a stirred solution oftert-butylcarbazate (163 mg, 1.24 mmol) in tetrahydrofuran (5 ml) atroom temperature under a nitrogen atmosphere. After 18 hours the solventwas removed in vacuo and the residue dissolved in dichloromethane (3ml). The solution was passed through a short plug of silica washing with20 ml of a 95/5 mixture of dichloromethane/methanol. The solvent wasagain removed in vacuo and the residue redissolved in tetrahydrofuran (8ml). Concentrated hydrochloric acid (1.9 ml) and water (0.6 ml) wereadded and the mixture was heated on a steam bath for 1 hour. Aftercooling the mixture was poured into water (100 ml), the pH adjusted topH 6 and the product extracted with dichloromethane (2×100 ml). Theorganic layers were dried (MgSO₄) and concentrated. The yellow residuewas redissolved in tetrahydrofuran (8 ml) and N,N-carbonyl diimidazolyl(121 mg, 0.74 mmol) and triethylamine (0.095 ml, 0.68 mmol) were added.After 18 hours the solution was poured into aqueous ammonium chloride(100 ml) and extracted with dichloromethane (2×100 ml). The organiclayers were dried (MgSO₄) and concentrated in vacuo to give a yellowoil. Flash column chromatography (eluting with 97% dichloromethane, 3%methanol) gave the title compound as a yellow foam.

¹ H NMR (300 MHz. CDCl₃):δ=1.25 (d, 6H), 1.45 (t, 3H), 3.00 (m, 1H),4.10 (q, 2H), 5.00 (s, 1H), 5.90 (s, 2H), 6.65 (s, 1H), 6.70 (d, 1H),7.00 (s, 1H), 7.20 (d, 1H), 7.40 (d, 1H), 7.40 (d, 2H), 7.45 (d, 1H),7.80 (s, 1H), 7.90 (d, 2H), 8.40 (s, 1H), 8.60 (s, 1H)

LRMS (Thermospray: 606.4 (MH⁻)

EXAMPLE 12N-(4-Iso-propylbenzenesulphonyl)-2-[3-(1-ethyl-6-amido)indolyl]-2-(3,4-methylenedioxyphenyl)acetamide##STR24##

N,N-carbonyldiimidazole (98 mg, 0.60 mmol) was added to a stirredsolution ofN-(4-iso-propylbenzenesulphonyl)-2-[3-(1-ethyl-6-carboxy)indolyl]-2-(3,4-methylenedioxyphenyl)acetamide (the title compound of Example 4. 300 mg, 0.55 mmol), in drytetrahydrofuran (8 ml) under nitrogen. The solution was heated to refluxfor 12 hours then cooled to room temperature. Ammonia (gas) was bubbledthrough the solution for 10 minutes and the flask was securely stopperedand stirring continued for a further 48 hours during which time a yellowprecipitate formed. The solvent was removed in vacuo and the residuedissolved in dichloromethane (50 ml) the organic layer was washed withaqueous ammonium chloride and then brine before drying (magnesiumsulphate) and concentrating in vacuo. The yellow residue was trituratedwith 5% methanol and 95% dichloromethane to give the product as a paleyellow solid.

¹ H NMR (400 MHz. CD₃ OD):δ=1.25 (d, 6H), 1.40 (t, 3H), 3.00 (sep, 1H),4.20 (q, 2H), 5.05 (s, 1H), 5.90 (s, 1H), 6.65 (s, 1H), 6.70 (s, 2H),7.00 (s, 1H), 7.20 (d, 1H), 7.40 (d, 2H), 7.45 (d, 1H), 7.80 (d, 2H),8.00 (s, 1H).

LRMS (Thermospray: 548.0 (MH⁺)

EXAMPLE 13N-(4-Iso-propylbenzenesulphonyl)-2-[3-(1-methyl-6-carboxy)indolyl]-2-(3,4-methylenedioxyphenyl)acetamide

(a) 6-Bromo-1-methylindole ##STR25##

Sodium hydride (4.10 g of a 60% dispersion in paraffin wax) was added toa stirred solution of 6-bromoindole (10 g, 51.3 mmol) in tetrahydrofuran(100 ml) at 0° C. under a nitrogen atmosphere. After 1 hour iodomethane(6.38 ml, 102.6 mmol) was added and the cooling bath removed. After 12hours methanol was added dropwise until effervescence ceased and thenthe solvent was removed in vacuo. The thick residue was diluted withdichloromethane and washed first with water then with brine. The organiclayer was dried (magnesium sulphate) and concentrated in vacuo to give adark yellow oil. Filtration through a plug of silica with 90% hexane/10%ethyl acetate as eluant gave the subtitle compound as a pale yellow oil(10.5 g).

¹ H NMR (300 MHz. CDCl₃):δ=3.75 (d, 3H), 6.40 (d, 1H), 7.00 (d, 1H),7.20 (d, 1H), 7.50 (d, 1H), 7.45 (s, 1H).

LRMS (Thermospray: 209.7 (MH⁺)

(b)N-(4-Iso-propylbenzenesulphonyl)-2-[3-(1-methyl-6-carboxy)indolyl]-2-(3,4-methylenedioxyphenyl)acetamide##STR26##

N-(4-Iso-propylbenzenesulphonyl)-2-[3-(1-methyl-6-methoxycarbonyl)indolyl]-2-(3,4-methylenedioxyphenyl)acetamidewas prepared by the methods of Examples 1 (b), 1(d), 2 and 3, butstarting with the subtitle compound of step (a) in place of6-bromo-1-ethylindole. Then, aqueous KOH (7.3 ml of a 1M solution) wasadded to a stirred solution of this product (2 g, 3.65 mmol) in methanol(50 ml) and the solution was heated at reflux for 8 hours. After coolingthe methanol was removed in vacuo and the resulting solution waspartitioned between 1M hydrochloric acid (100 ml) and dichloromethane(3×100 ml).

The organic fractions were dried (MgSO₄) and concentrated to give ayellow solid. Flash column chromatography (using 95% dichloromethane/5%methanol as eluant) gave the title compound as a white solid (1.44 g).

¹ H NMR (400 MHz. CDCl₃):δ=1.25 (d, 6H), 3.00 (hept, 1H), 3.80 (s, 3H),5.05 (s, 1H), 5.95 (s, 2H), 6.65 (d, 2H), 6.70 (s, 1H), 7.00 (s, 1H),7.20 (d, 1H), 7.40 (d, 2H), 7.65 (d, 1H), 7.90 (d, 2H), 8.05 (s, 1H).

LRMS (Thermospray: 552.7 (MNH₄ ⁺)

Examples 14-18 were prepared using the method of Example 13(b), butusing the appropriate aromatic sulphonamide in place of4-isopropylbenezenesulphonamide in the method of Example 3.

    __________________________________________________________________________      #STR27##                                                                      #STR28##                                                                    Example                                                                         N.sup.0 Ar Physical Data                                                    __________________________________________________________________________      14                                                                                            #STR29##                                                                    .sup.1 H NMR (300 MHz CDCl.sub.3): δ = 3.80 (s,                         3H),  5.00 (s, 1H), 5.90 (s, 2H), 6.60 (s, 1H), 6.65 (d,                      2H), 7.00 (s, 1H), 7.10 (d, 1H), 7.45 (m, 2H),  7.60 (m,                      2H), 7.90 (d, 2H), 8.00 (s, 1H), 8.80  (brs, 1H).  LRMS                       (Thermospray): 493.1 (MH.sup.+).                                 - 15                                                                                         .sup.1 H NMR (400 MHz, CDCl.sub.3): δ = 3.80 (s,                      3H),  5.00 (s, 1H), 6.00 (s, 2H), 6.65 (m, 3H), 7.00 (s,                      1H), 7.20 (d, 1H), 7.50 (d, 2H), 7.70 (d, 1H),  7.90 (d,                      2H), 8.05 (s, 1H), 8.45 (brs, 1H).  LRMS (APCI): 527.0,                       527.8 (MH.sup.+).                                                - 16                                                                                         .sup.1 H NMR (400 MHz, CDCl.sub.3): δ = 3.80 (s,                      3H),  5.00 (s, 1H), 5.90 (s, 2H), 6.65 (m, 3H), 7.00 (s,                      1H), 7.20 (d, 1H), 7.65 (d, 1H), 7.80 (d, 2H),  8.00 (s,                      1H), 8.10 (d, 2H), 9.00 (s, 1H),  LRMS (APCI): 592.9                          (MNH.sub.4.sup.+).                                               - 17*                                                                                        .sup.1 H NMR (400 MHz, CDCl.sub.3): δ = 2.40 (s,                      3H),  3.40 (s, 3H), 3.75 (s, 3H), 5.05 (s, 1H), 5.90 (d,                      2H), 6.45 (s, 1H), 6.70 (d, 1H), 6.75 (d, 1H),  6.85 (d,                      1H), 7.10 (s, 1H), 7.30 (m, 3H), 7.60 (d,  1H), 7.90 (d,                      1H), 8.00 (s, 1H), 9.20 (brs, 1H).  LRMS (APCI): 537.0                        (MH.sup.+).                                                      - 18                                                                                         .sup.1 H NMR (300 MHz, CD.sub.3 OD): δ = 3.75 (s,                     3H),  4.95 (s, 1H), 5.95 (d, 2H), 6.65 (s, 1H), 6.75 (s,                      2H), 7.15 (s, 1H), 7.25 (d, 1H), 7.65 (d, 1H),  7.95 (d,                      2H), 8.05 (d, 2H), 8.10 (s, 1H),  LRMS (APCI): 518.3                          (MH.sup.+).                                                      - 19                                                                                         .sup.1 H NMR (300 MHz, CDCl.sub.3): δ = 2.45 (s,                      3H),  3.80 (s, 3H), 5.00 (s, 1H), 5.95 (s, 2H), 6.65 (m,                      3H), 7.00 (s, 1H), 7.15 (d, 1H), 7.30 (d, 2H),  7.60 (d,                      1H), 7.80 (d, 2H), 8.00 (s, 1H), 8.70 (s,  1H).  LRMS                         (APCI): 507.3 (MH.sup.+).                                        - 20                                                                                         .sup.1 H NMR (300 MHz, d.sub.6 -DMSO): δ = 3.64                       (s,  3H), 5.23 (s, 1H), 5.92 (s, 2H), 6.52 (s, 1H), 6.60                      (d, 1H), 6.68 (d, 1H), 6.90 (s, 1H), 7.03 (d, 1H),  7.35                      (d, 1H), 7.60 (dd, 1H), 7.75 (dd, 1H), 7.90  (s, 1H),                         8.30 (d, 1H), 8.40 (d, 1H), 8.49 (d, 1H),  8.80 (d, 1H).                      LRMS (APCI): 543.8 (MH.sup.+)  m.p.: 238-240° C.                       dec.                                                          __________________________________________________________________________     *See Preparation 11 for preparation of aromatic sulphonamide             

Examples 21-24 were prepared by the method of Example 12 from thecompounds of Examples 14, 15, 16 and 20 respectively.

    __________________________________________________________________________      #STR36##                                                                      #STR37##                                                                    Example                                                                         N.sup.0 Ar Physical Data                                                    __________________________________________________________________________      21                                                                                            #STR38##                                                                    .sup.1 H NMR (400 MHz, CD.sub.3 OD): δ = 3.70 (s,                       3H),  5.05 (s, 1H), 5.80 (s, 2H), 6.80 (m, 3H), 6.85 (s,                      1H), 7.20 (m, 2H), 7.40 (m, 3H), 7.90 (m, 3H).  LRMS                          (APCI): 492 (MH.sup.+).                                          - 22                                                                                         .sup.1 H NMR (400 MHz, CD.sub.3 OD): δ = 3.65 (s,                     3H),  5.05 (s, 1H), 5.80 (d, 2H), 6.85 (m, 3H), 6.95 (s,                      1H), 7.20 (d, 1H), 7.40 (d, 2H), 7.45 (d, 1H), 7.80  (d,                      2H), 7.95 (s, 1H).  LRMS (APCI): 525.9, 526.7 (MH.sup.+).        - 23                                                                                         .sup.1 H NMR (300 MHz, CD.sub.3 OD): δ = 3.70 (s,                     3H),  5.00 (s, 1H), 5.80 (s, 2H), 6.60 (d, 1H), 6.70 (s,                      1H), 6.75 (d, 1H), 7.00 (s, 1H), 7.30 (d, 1H),  7.40  (d,                     1H), 7.65 (d, 2H), 7.90 (s, 1H), 8.00 (d, 2H).  LRMS                          (APCI): 560.9 (MH.sup.+).                                        - 24                                                                                         .sup.1 H NMR (400 MHz, d.sub.6 -DMSO): δ = 3.64                       (s, 3H),  4.87 (s, 1H), 5.90 (d, 2H), 6.64 (d, 1H), 6.65                      (d,  1H), 6.76 (s, 1H), 7.02 (s, 1H), 7.09 (brs, 1H),                         7.20 (d, 1H), 7.35 (d, 1H), 7.55 (dd, 1H), 7.60 (dd,                          1H), 7.78 (brs, 1H), 7.90 (s, 1H), 8.08 (d, 1H),  8.29                        (d, 1H), 8.39 (d, 1H), 8.90 (d, 1H),  Analysis: Found: C,                     57.98: H,                                                         4.62: N, 11.58.  C.sub.28 H.sub.22 N.sub.4 OS: NH.sub.3 : H.sub.2 O:                      Requires: C, 58.22: H, 4.71: N, 12.12.                        __________________________________________________________________________

Examples 25-26 were prepared by the method of Example 5 from thecompound of Example 17 and the appropriate amine.

    __________________________________________________________________________      #STR42##                                                                      #STR43##                                                                    Example                                                                         N.sup.0 R.sub.7 R.sub.8 N Physical Data                                     __________________________________________________________________________      25                                                                                                   #STR44##                                                                    .sup.1 H NMR (400 MHz, d.sub.6 -DMSO): δ =                              2.70 (s,  3H), 2.80 (d, 3H), 3.60 (s, 3H), 3.80                               (s, 3H), 5.20  (s, 1H), 5.95 (s, 2H), 6.70 (d,                                1H), 6.75 (s, 1H),  6.80 (d, 1H), 6.95 (s, 1H),                               7.05 (s, 1H), 7.20 (d,  1H), 7.40 (d, 1H), 7.65                               (d, 1H), 7.90 (s, 1H), 8.25  (s, 1H), 12.3 (brs,                              1H).  LMRS (APCI): 550.4 (MH.sup.+).                      - 26                                                                                                .sup.1 H NMR (400 MHz, CD.sub.3 OD): δ =                              2.45 (s, 3H),  2.50 (s, 3H), 2.60 (brs, 4H), 3.65                             (s, 3H), 3.70  (brs, 4H), 3.80 (s, 3H), 5.15 (s,                              1H), 5.90 (s, 2H),  6.70 (s, 1H), 6.80 (m, 2H),                               6.95 (s, 1H), 7.00 (d,  1H), 7.05 (s, 1H), 7.10                               (d, 1H), 7.40 (d, 1H), 7.55  (s, 1H), 7.85 (d,                                1H),  LRMS (APCI): 619.9 (MH.sup.+).                   __________________________________________________________________________

EXAMPLE 272-(Dimethylamino)ethyl3-[1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl]-1-methyl-1H-6-indolecarboxylate##STR46##

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (128 mg,0.67 mmol) was added to a stirred solution of3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-6-indolecarboxylicacid (the product of Example 17, 300 mg, 0.56 mmol),N,N-dimethylaminopyridine (75 mg, 0.61 mmol) and dimethylaminoethanol(0.17 ml, 1.67 mmol) in a mixture of CH₂ Cl₂ (9 ml) and DMF (0.5 ml) atroom temperature under a nitrogen atmosphere. After 12 h a fine whiteprecipitate had formed. The product was removed by filtration and washedwith cold methanol.

¹ H NMR (400 MHz. d₆ -DMSO):δ=2.40 (s, 9H), 2.70 (t, 2H), 3.60 (s, 3H),3.75 (s, 3H), 4.30 (t, 2H), 5.05 (s, 1H), 5.90 (s, 2H), 6.65 (d, 1H),6.70 (s, 1H), 6.75 (d, 1H), 6.80 (d, 1H), 6.85 (s, 1H), 7.20 (s, 1H),7.30 (d, 1H), 7.50 (d, 1H), 7.60 (d, 1H), 8.00 (s, 1H).

LRMS (APCI): 608.9 (MH⁺)

EXAMPLE 283-{1-(1,3-Benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-6-indolecarboxamide

(a) 3-Nitro-4-methylbenzoic acid tert-butyl ester ##STR47##

To a solution of 3-nitro-4-methylbenzoic acid (17.3 g 96 mmol) indichloromethane (250 ml) and tert-butanol (35.8 g 470 mmol) at 0° C.under nitrogen was added 4-dimethylaminopyridine (6 g 50 mmol) and1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25.8 g 140mmol) and the solution allowed to come to room temperature over 1 hour,then stirred overnight. The solution was poured into 1:1 ethylacetate:water (800 ml each) and the organic layer washed with aqueousbicarbonate and saturated aqueous sodium chloride, then dried (MgSO₄)and evaporated, to give the product as a clear oil (22.6 g).

¹ H NMR (300 MHz CDCl₃): 1.60 (s, 9H), 2.65 (s, 3H), 7.40 (d, 1H), 8.10(d, 1H), 8.55 (s, 1H).

LRMS (Thermospray): 238.4 (MH⁻)

(b) Indole 6-tert-butyl ester ##STR48##

To a solution of the ester from step (a) (23 g 97 mmol) indimethylformamide (100 ml) was added dimethylformamidedimethyl acetal(50 ml) and pyrrolidine (20 drops). The solution was stirred undernitrogen at 80° C. overnight to give a dark red solution, which wasevaporated to dryness to give a dark red oil, which crystallised onstanding and was used without further purification.

The crude dimethyl enamine (assumed 97 mmol) was dissolved in toluene(850 ml) and hydrogenated overnight at a pressure of 345 kPa (50 psi) inthe presence of 10% palladium-on-charcoal (5 g). Catalyst was removed byfiltration and solvents evaporated. The residue was chromatographed onflash silica using dichloromethane eluent to give product as acrystalline solid (12.6 g).

¹ H NMR (400 MHz CDCl₃): 1.65 (s, 9H), 6.60 (s, 1H), 7.40 (t, 1H), 7.65(d, 1H), 7.80 (d, 1H), 8.15 (s, 1H), 8.50 (s, 1H).

(c) 1-Methylindole 6-tert-butyl ester ##STR49##

To a solution of the indole from step (b) (12.5 g 57 mmol) intetrahydrofuran (150 ml) at 0° C. under nitrogen was added sodiumhydride as a 60% suspension in oil (2.28 g, 57 mmol). When effervescenceceased, methyl iodide (3.6 ml, 57 mmol) was added and the solutionallowed to come to room temperature. The mixture was stirred for 1 hour,poured into ethyl acetate (500 ml), and washed with water and saturatedbrine, then dried (MgSO₄) and evaporated to give an oil which wascontaminated with hydride oil, but sufficiently pure to continue (14.1g).

¹ H NMR (300 MHz CDCl₃): 1.65 (s, 9H), 3.85 (s, 3H(, 6.50 (d, 1H), 7.20(s, 1H), 7.60 (d, 1H), 7.75 (d, 1H), 8.05 (s, 1H).

LRMS (Thermospray): 232.2 (MH⁻)

(d)Ethyl-2-[3-(1-methyl-6-carboxy)indolyl]-2-(3,4-methylenedioxyphenyl)acetat##STR50##

To a solution of boron trifluoride diethyl etherate (14 ml 132 mmol) andtriethylsilane (40 ml 240 mmol) in dichloromethane (60 ml) at -78° C.under nitrogen was added a solution of the indole from (c) (14 g 60mmol) and benzodioxole ethylpyruvate (14 g, 66 mmol) in dichloromethane(80 ml) dropwise. The solution was stirred at -78° C. for 30 minutes,then quenched with aqueous hydrochloride acid and the organic layerseparated, dried (MgSO₄) and evaporated. The hydroxy intermediate wasisolated by flash chromatography using 30% ethyl acetate in hexaneeluant as a buff solid (19.38 g). This intermediate (15 g) was dissolvedin dichloromethane (50 ml) and triethyl silane (15 g) at 0° C. undernitrogen, and trifluoroacetic acid (50 ml) was added dropwise over 10minutes. After 1 hour at room temperature the reaction was quenched withwater, and the organic layer separated, dried (MgSO₄) and evaporated.Chromatography on flash silica using ethyl acetate eluant gave the acidester as a pale foam (9.53 g).

¹ H NMR (400 MHz CDCl₃): 1.25 (t, 3H), 3.85 (s, 3H), 4.20 (m, 2H), 5.20(s, 1H), 5.95 (s, 2H), 6.70-8.20 (m, 7H).

(e) Ethyl2-(1,3-Benzodioxol-5-yl)-2-(6-carbamoyl-1-methyl-1H-3-indolyl)acetate##STR51##

To a solution of the acid (9.43 g, 25 mmol) in tetrahydrofuran (125 ml)was added carbonyldiimidazole (4.0 g 25 mmol) and the solution refluxedfor 4 hours. The solution was cooled to 0° C. and saturated with gaseousammonia then stirred overnight. The reaction was concentrated in vacuoand partitioned between ethyl acetate and water. The organic layer waswashed twice with water and brine, then dried (MgSO₄ 0 and evaporated.Product was isolated by flash chromatography using 2% methanol indichloromethane eluant to give the amide ester as a pale foam (5.6 g).

¹ H NMR (300 MHz d₆ -DMSO): 1.20 (t, 3H), 3.80 (s, 3H), 4.15 (q, 2H),5.20 (s, 1H), 5.95 (d, 2H), 6.80-8.00 (m, 9H).

LRMS (Thermospray): 281.1 (MH⁻)

(f) 2-(1,3-Benzodioxol-5-yl)-2-(6-carbamoyl-1-methyl-1H-3-indolyl)aceticacid ##STR52##

To a solution of the amide ester from step (e) (5.6 g 14.7 mmol) intetrahydrofuran (60 ml) and methanol (30 ml) was added aqueous sodiumhydroxide solution (10 ml of 5M, 50 mmol) dropwise, and the mixtureheated at reflux for 9 hours. Solvents were removed in vacuo and theresidue dissolved in aqueous sodium hydroxide and washed withdichloromethane. The aqueous layer was acidified with aqueoushydrochloric acid and the product isolated by filtration. Triturationwith ethyl acetate gave the product as a white solid (5.1 g).

¹ H NMR (300 MHz d₆ -DMSO): 3.80 (s, 3H), 5.15 (s, 1H), 6.00 (d, 2H),6.80-8.00 (m, 9H).

LRMS (Thermospray): 353.5 (MH⁻)

(g)3-{(1-(1,3-Benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-6-indolecarboxamide##STR53##

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (65 mg, 0.34mmol) was added to a stirred solution.2-(1,3-benzodioxol-5-yl)-2-(6-carbamoyl-1-methyl-1H-3-indolyl)aceticacid (from step (f). 100 mg, 0.28 mmol), dimethylaminopyridine (45 mg,0.37 mmol) and p-toluenesulphonamide (53 mg, 0.31 mmol) indichloromethane (5 ml) and dimethylformamide (1 ml) at room temperatureunder a nitrogen atmosphere. After 14 h the solvent was removed in vacuoand the product was extracted from 1N hydrochloric acid (50 ml) withethyl acetate (2×50 ml). The organic layers were dried and concentratedto give a fawn foam. Flash column chromatography (elution with 95%dichloromethane/5% methanol) gave the product (95 mg) as a white solid.

¹ H NMR (300 MHz, CD₃ OD): δ=2.40 (s, 3H), 3.75 (s, 3H), 5.05 (s, 1H),5.90 (s, 2H), 6.60 (m, 3H), 6.90 (s, 1H), 7.20 (d, 1H), 7.30 (d, 2H),7.40 (d, 1H), 7.80 (d, 2H), 7.95 (s, 1H).

LRMS (APCI): 506 (MH⁺)

Examples 29-45 were prepared by reacting the compound of Example 28(f)with the appropriate aromatic sulphonamide using the method of Example28(g).

    __________________________________________________________________________      #STR54##                                                                    Example                                                                         N.sup.0 Ar Physical Data                                                    __________________________________________________________________________      29                                                                                                #STR55##                                                                    .sup.1 H NMR (400 MHz, d.sub.6 -DMSO): δ = 2.35                         (s,  3H), 3.60 (s, 3H), 3.75 (s, 3H), 5.20 (s, 1H),                           5.95 (d, 2H), 6.60-8.00 (m, 12H),  LRMS (Thermospray)                         536.4 (MH.sup.+)                                             - 30                                                                                             .sup.1 H NMR (300 MHz, CD.sub.3 OD): δ = 2.45                         (s, 3H),  3.80 (s, 3H), 5.00 (s, 1H), 5.85 (s, 2H),                           6.90  (m, 4H), 7.00 (s, 1H), 7.20 (d, 1H), 7.40 (d,                           1H), 7.50 (d, 1H), 7.90 (s, 1H).  LRMS (APCI): 512.1                          (MH.sup.+).                                                  - 31                                                                                             .sup.1 H NMR (300 MHz, CD.sub.3 OD): δ = 3.10                         (s,  6H), 3.60 (s, 3H), 5.00 (s, 1H), 5.80 (s, 2H),                           6.45 (d, 1H), 6.65 (m, 3H), 7.00 (s, 1H), 7.20  (d,                           1H), 7.40 (d, 1H), 7.80 (d, 1H), 7.90 (s,  1H), 8.50                          (s, 1H).  LRMS (APCI): 536.2 (MH.sup.+).                     - 32                                                                                             .sup.1 H NMR (300 MHz, d.sub.6 -DMSO): δ =                            3.70 (s,  3H), 4.80 (s, 1H), 5.90 (d, 2H), 6.65 (d,                           1H),  6.70 (d, 1H), 6.80 (s, 1H), 7.10-7.40 (m, 5H),                          7.90 (s, 1H), 8.00 (d, 1H), 8.50 (d, 1H), 6.80 (s,                            1H).  LRMS (APCI): 493.8 (MH.sup.+).                         - 33                                                                                             .sup.1 H NMR (400 MHz, CD.sub.3 OD): δ = 3.80                         (s,  3H), 4.00 (s, 3H), 5.00 (s, 1H), 5.80 (s, 2H),                           6.70 (d, 1H), 6.80 (m, 2H), 7.20 (m, 4H).  LRMS                               (APCI) 498 (MH.sup.+).                                       - 34                                                                                             .sup.1 H NMR (400 MHz, d.sub.6 -DMSO): δ =                            3.75 (s,  3H), 5.05 (s, 1H), 5.95 (s, 2H), 6.70 (d,                           1H),  6.75 (s, 1H), 6.80 (d, 1H), 7.05 (s, 1H), 7.20                          (d,  1H), 7.45 (d, 1H), 7.60 (t, 1H), 7.75 (m, 3H),                           8.00 (s, 1H).  LRMS (Thermospray): 525.7, 527.3                               (MH.sup.+).                                                  - 35                                                                                             .sup.1 H NMR (300 MHz, CDCl.sub.3): 3.85 (s, 3H),                           4.70  (s, 2H), 5.15 (s, 1H), 6.00 (s, 2H), 6.80-8.00                          (m, 11H), 11.95 (s, 1H),  LRMS (Thermospray): 505.4                           (MH.sup.+)                                                   - 36                                                                                             .sup.1 H NMR (300 MHz, d.sub.6 -DMSO): 3.65 (s,                             3H),  3.75 (s, 3H), 5.20 (s, 1H) 5.95 (d, 2H) 6.60-                           8.00 (m, 12H), 12.60 (s, 1H).  LRMS (Thermospray):                            555.7 (MH.sup.+)                                             - 37                                                                                             .sup.1 H NMR (400 MHz, CDCl.sub.3): δ = 1.10                          (t, 3H),  3.55 (s, 2H), 3.60 (s, 3H), 4.00 (q, 2H),                           4.80 (s,  1H), 5.75 (s, 2H), 6.60 (s, 3H), 6.80 (s,                           1H),  7.00 (d, 1H), 7.25 (m, 3H), 7.75 (s, 1H), 7.80                          (d, 2H).  LRMS (APCI): 578.5 (MH.sup.+).                     - 38                                                                                             .sup.1 H NMR (400 MHz, CDCl.sub.3): δ = 2.50                          (s, 3H),  3.70 (s, 3H), 5.05 (s, 1H), 5.80 (s, 2H),                           6.60 (d,   1H), 6.70 (d, 1H), 6.75 (s, 1H), 7.00 (s,                          1H),  7.05 (d, 1H), 7.10 (d, 1H), 7.25 (d, 1H), 7.85                          (s,  1H), 7.90 (d, 1H),  LRMS (APCI): 508.0 (MH.sup.+)                        .                                                            - 39                                                                                             .sup.1 H NMR (400 MHz, d.sub.6 -DMSO): 3.65 (s,                             3H),  3.75 (s, 3H), 5.20 (s, 1H), 5.95 (d, 2H), 6.60-                          8.00 (m, 13H), 12.40 (s, 1H).                               - 40‡                                                                                 .sup.1 H NMR (400 MHz, d.sub.6 -DMSO): 2.40 (s,                             3H),  3.65 (s, 3H), 3.80 (s, 3H), 5.20 (s, 1H), 5.95                          (d,  (2H), 6.60-8.00 (m, 11H), 12.50 (s, 1H).                                   - 41*                                                                         .sup.1 H NMR (400 MHz, CD.sub.3 OD): δ = 2.45                         (t, 3H),  3.75 (s, 3H), 4.35 (q, 2H), 5.15 (s, 1H),                           5.95 (s,  2H), 6.80 (m, 4H), 6.95 (s, 1H), 7.35 (d,                           1H),   7.55 (d, 1H), 7.75 (d, 2H), 7.80 (s, 1H), 7.95                         (d,   2H), 8.00 (s, 1H).                                     - 42†                                                                                     .sup.1 H NMR (400 MHz, d.sub.6 -DMSO): δ =                            3.40 (s,  3H), 3.80 (s, 3H), 5.20 (s, 1H), 6.00 (s,                           2H),  6.70 (d, 1H), 6.75 (s, 1H), 6.80 (d, 1H), 7.00                          (s,  1H), 7.20 (m, 2H), 7.45 (d, 1H), 7.80 (m, 2H),                           7.95 (s, 1H), 8.45 (s, 1H).  LRMS (APCI): 506.7                               (MH.sup.+).                                                  - 43                                                                                             .sup.1 H NMR (400 MHz, CD.sub.3 OD): δ = 3.70                         (s,  3H), 3.95 (s, 3H), 5.00 (s, 1H), 5.80 (s, 2H),                           6.60 (d, 1H), 6.80 (s, 1H), 6.85 (d, 1H), 7.05 (s,                            1H), 7.25 (d, 1H), 7.40 (d, 1H), 7.80 (d, 2H),  7.90                          (s, 1H), 7.95 (d, 2H).  LRMS (Thermospray): 550.0                             (MH.sup.+).                                                  - 44                                                                                             .sup.1 H NMR (400 MHz, CD.sub.3 OD): δ = 2.70                         (m,  2H), 2.75 (s, 3H), 2.85 (m, 2H), 3.75 (m, 4H),                           3.95 (s, 3H), 5.25 (s, 1H), 6.00 (d, 2H), 6.80  (m,                           3H), 7.10 (s, 1H), 7.40 (d, 1H), 7.50 (d,  1H), 7.60                          (d, 1H), 8.05 (s, 1H), 8.30 (d, 1H),  8.80 (s, 1H),                           LRMS (APCI): 619.9 (MH.sup.+).                               - 45                                                                                             .sup.1 H NMR (300 MHz, d.sub.6 -DMSO): δ =                            3.70 (s,  3H), 3.75 (s, 3H), 4.96 (br, 1H), 5.90 (d,                          2H),  6.70-6.78 (m, 2H), 6.84 (s, 1H), 7.10 (brs,                             1H),                                                          7.22 (s, 1H), 7.32 (d, 1H), 7.40-7.60 (m, 4H).  7.80 (brs, 1H)                                7.90-7.95 (m, 2H), 12.50 (brs,  1H exchangeable).                             Analysis: Found: C, 54.90: H, 3.94: N, 6.98.                                  C.sub.27 H.sub.23 N.sub.2 O.sub.8 S; 0.6 CH.sub.2                             Cl.sub.2                                                      Requires: C, 55.20: H, 4.06: N, 7.00.                                     __________________________________________________________________________     ‡See Preparation 8 for sulphonamide preparation                    *See Preparation 3 for sulphonamide preparation                               †See Preparation 4 for sulphonamide preparation                   

EXAMPLE 46

Ethyl-3-(4-[2-(6-carbamoyl-1-methyl-1H-3-indolyl)-2-(1,3-benzodioxol-5-yl)acetyl]sulfamoylphenyl)propanoate##STR72##

Ethyl(E)-3-(4-[2-(6-carbamoyl-1-methyl-1H-3-indolyl)-2-(1,3-benzodioxol-5-yl)acetyl]sulfamoylphenyl)-2-propenoate(the compound of Example 41, 0.24 g, 0.40 mmol) was dissolved in ethanol(5 ml) and 5% palladium-on-carbon (24 mg) was added. The mixture wasplaced in a pressure vessel and a hydrogen pressure of 345 kPA (50 psi)was maintained for 48 h. The reaction mixture was filtered throughArbocel™ and concentrated in vacuo. Flash column chromatography (elutionwith 5% methanol/90% dichloromethane) gave the product (70 mg).

¹ H NMR (400 MHz CD₃ OD): δ=1.20 (t, 3H), 2.60 (t, 2H), 3.00 (t, 2H),3.75 (s, 3H), 4.05 (q, 2H), 5.05 (s, 1H), 5.85 (s, 2), 6.60 (s, 1H),6.70 (s, 2H), 6.90 (s, 1H), 7.20 (d, 1H), 7.30 (d, 2H), 7.40 (d, 1H),7.80 (d, 2H), 7.90 (s, 1H).

LRMS (APCI): 591.9 (MH⁻).

EXAMPLE 47

2-(4-[2-(1,3-Benzodioxol)-5-yl)-2-(6-carbamoyl-1-methyl-1H-3-indolyl)acetyl]-sulfamoylphenyl)aceticacid ##STR73##

1M sodium hydroxide solution (0.57 ml) was added to a stirred solutionof ethyl2-(4-[2-(1,3-benzodioxol-5-yl)-2-(6-carbamoyl-1-methyl-1H-3-indolyl)acetyl]sulfamoylphenyl)acetate (the product of Example 37, 110 mg, 0.19 mmol) in aqueous dioxan(8 ml dioxan:2 ml H₂ O) at room temperature. After 1 h the solvent wasremoved in vacuo. The reaction mixture was diluted with ethyl acetateand poured into 0.5m hydrochloric acid (50 ml) and extracted with ethylacetate (2×50 ml). The organic layers were dried (magnesium sulphate)and concentrated in vacuo to give a yellow foam. Flash columnchromatography (elution with 95% dichloromethane/5% methanol) gave theproduct as a white solid (90 mg).

¹ H NMR (400 MHz, CDCl₃): δ=3.40 (s, 2H), 3.90 (s, 3H), 5.20 (s, 1H),6.00 (s, 2H), 6.80 (m, 3H), 7.00 (s, 1H), 7.30 (d, 1H), 7.60 (d, 2H),7.65 (s, 1H, 8.00 (s, 1H), 8.10 (d, 2H).

LRMS (APCI): 549.9 (MH⁺).

Examples 48-50 were made using the method of Example 47, starting withthe compounds of Examples 45, 43 and 46 respectively.

    __________________________________________________________________________      #STR74##                                                                    Example                                                                         N.sup.0 Ar Physical Data                                                    __________________________________________________________________________      48                                                                                                #STR75##                                                                    .sup.1 H NMR (300 MHz d.sub.6 -DMSO): δ = 3.75                          (s,  3H), 5.26 (s, 1H) 5.96 (s, 2H), 6.70-6.82 (m,                            3H), 7.10-7.17 (m, 2H), 7.27 (d, 1H), 7.46  (d, 1H),                          7.60-7.86 (m, 4H), 7.96 (s, 1H), 8.00  (d, 1H).  LRMS                         (APCI): 536.1 (MH.sup.+).                                    - 49                                                                                             .sup.1 H NMR (400 MHz, CD.sub.3 OD): δ = 3.80                         (s,  3H), 5.05 (s, 1H), 5.80 (d, 2H), 6.60 (s, 1H),                           6.70 (d, 1H), 6.75 (d, 1H), 6.90 (s, 1H), 7.20  (d,                           1H), 7.40 (d, 1H), 7.85 (s, 1H), 7.90 (d,  2H), 8.00                          (d, 2H),  LRMS (APCI): 536.0 (MH.sup.+).                     - 50                                                                                             .sup.1 H NMR (300 MHz, CD.sub.3 OD): δ = 2.80                         (t,  2H), 3.00 (t, 2H), 3.75 (s, 3H), 5.00 (s, 1H),                           5.80 (d, 2H), 6.60 (m, 3H), 6.90 (s, 1H), 7.20  (d,                           1H), 7.30 (d, 2H), 7.40 (d, 1H), 7.80 (d,  2H), 7.90                          (s, 1H),  LRMS (APCI): 563.8 (MH.sup.+).                  __________________________________________________________________________

EXAMPLE 51

3-1-(1,3-Benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl-6-cyano-1-methyl-1H-indole

(a) 6-cyano-1-methylindole ##STR78##

Cuprous cyanamide (12.8 g, 143 mmol) was added to a stirred solution of6-bromo-1-methylindole (10 g, 47 mmol) in N-methypyrrolidinone (60 ml)under a nitrogen atmosphere. The reaction mixture was heated at 150° C.for 48 h. The reaction mixture was cooled and partitioned between ethylacetate (200 ml) and aqueous ammonia (200 ml of 0.88M). The organiclayer was washed with brine (3'200 ml), dried (MgSO₄) and concentrated.Flash column chromatography (elution with 70% hexane/30% ethyl acetate)gave the product as a crystalline white solid (5.3 g).

¹ H NMR (400 MHz, CDCl₃): δ=3.80 (s, 3H), 6.60 (s, 1H), 7.25 (d, 1H),7.35 (d, 1H), 7.70 (d, 2H).

LRMS (Thermospray): 174.1 (MNH₄ ⁺).

(b)3-[1-(1,3-Benzodioxol-5-yl)-2-[(4-isoproylphenyl)sulfonamido]-2-oxoethyl]-6-cyano-1-methyl-1H-indole##STR79##

The title compound was prepared using the methods of Examples 1(d), 2and 3, but starting with the compound of step (a) in place of6-methoxycarbonyl-1-ethylindole.

¹ H NMR (400 MHz, CDCl₃): δ=1.30 (d, 6H), 3.00 (m, 1H), 3.80 (s, 3H),5.00 (s, 1H), 6.00 (s, 2H), 6.60 (s, 1H), 6.65 (d, 1H), 6.70 (d, 1H),7.00 (s, 1H), 7.20 (s, 2H), 7.20 (d, 2H), 7.60 (s, 1H), 7.85 (d, 2H),8.20 (s, 1H).

LRMS (APCI): 516.2 (MH⁺).

EXAMPLE 52

3-[1-(1,3-Benzodioxol-5-yl)-2-[(4-iospropylphenyl)sulfonamido]-2-oxoethyl]-1-methyl-6-(2H-1,2,3,4-tetrazol-5-yl)-1H-indole##STR80##

Trimethylsilylazide (0.23 ml, 1.74 mmol) and dibutyl tin oxide (52 mg,0.2 mmol) were added to a solution of3-{1-(1,3-benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-6-cyano-1-methyl-1H-indole(the product of Example 51, 300 mg, 0.58 mmol) in toluene (10 ml) andthe solution was heated at reflux under an atmosphere of nitrogen for 14h. Tlc analysis showed incomplete reaction. Further aliquots oftrimethylsilylazide (0.23 ml, 1.74 mmol) and dibutyl tin oxide (52 mg,0.2 mmol) were added and heating was continued at reflux for a further24 h. The reaction was cooled and concentrated. The crude product waspurified by flash column chromatography (gradient elution from 95%dichloromethane /5% methanol to 90% dichloromethane /10% methanol)giving a pale pink solution (100 mg).

¹ H NMR (300 MHz, d₆ -DMSO): δ=1.20 (d, 6H), 3.00 (m, 1H), 3.80 (s, 3H),5.10 (s, 1H), 5.95 (s, 2H), 6.70 (d, 1H), 6.75 (s, 1H), 6.80 (d, 1H),7.10 (s, 1H), 7.25 (d, 1H), 7.40 (d, 2H), 7.60 (d, 1H), 7.75 (d, 2H),8.00 (s, 1H).

LRMS (APCI): 559 (MH⁺).

EXAMPLE 53

6-(Aminomethyl)-3-1-(1,3-benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl-1-methyl-1H-indole##STR81##

Sodium borohydride (213 mg, 5.6 mmol) was added slowly to a vigorouslystirred solution of3-{1-(1,3-benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-6-cyano-1-methyl-1H-indole(the product of Example 51, 290 mg, 0.56 mmol) and CoCl₂.6H₂ O (200 mg,0.84 mmol) in methanol (12 ml) at room temperature under a nitrogenatmosphere. After 2 h the reaction was complete and 2N hydrochloric acid(4 ml) was added dropwise. Stirring was continued until the blackprecipitate had dissolved. The methanol was removed in vacuo and theproduct was extracted from water with dichloromethane (50 ml) and ethylacetate (50 ml). The organic layers were combined, dried (MgSO₄ 0 andconcentrated. The crude product was purified by flash chromatography(elution with 90% dichloromethane /10% methanol /2% acetic acid) givinga brown gum. The residue was dissolved in methanol (10 ml) and stirredwith charcoal for 30 mins. Filtration and concentration gave the productas a yellow oil.

¹ H NMR (300 MHz, CD₃ OD): δ=1.20 (d, 6H), 2.95 (m, 1H), 3.65 (s, 3H),4.20 (s, 2H), 5.00 (s, 1H), 5.80 (d, 2H), 6.60 (d, 1H), 6.70 (d, 1H),6.75 (s, 1H), 6.80 (s, 1H), 7.00 (d, 1H), 7.25 (d, 3H), 7.40 (s, 1H),7.80 (d, 2H).

LRMS (Thermospray): 520.4 (MH⁺).

EXAMPLE 54

3-{(1-(1,3-Benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-6-(4,5-dihydro-1H-2-imidazolyl)-1-methyl-1H-indole##STR82##

Diethyldithiophosphate (1.3 ml, 7.7 mmol) was added to3-{1-(1,3-benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-6-cyano-1-methyl-1H-indole(the product of Example 51, 800 mg, 1.5 mmol) in a mixture of ethanol(10 ml) and water (5 drops). The reaction was heated at reflux withstirring for 14 h. After cooling the solvent was removed in vacuo andthe residues purified by flash column chromatography (elution with 98%dichloromethane /2% methanol) to give a brown oil. This residue wasdissolved in ethylenediamine and the reaction mixture heated at refluxfor 3 h. After cooling the ethylenediamine was removed in vacuo.Hydrochloric acid (10 ml) was added and the resulting precipitate wasfiltered and washed with dichloromethane and methanol. Flash columnchromatography (elution with 80% dichloromethane/20% methanol/5%NH₃)gave the product as a white solid.

¹ H NMR (300 MHz, d₆ -DMSO): δ=1.20 (d, 6H), 2.80 (m, 1H), 3.80 (s, 3H),3.95 (s, 4H), 4.80 (s, 1H), 5.85 (s, 2H), 6.70 (d, 1H), 6.75 (d, 1H),6.80 (s, 1H), 7.20 (d, 2H), 7.35 (s, 1H), 7.40 (d, 1H), 7.55 (d, 1H),7.60 (d, 2H), 8.05 (s, 1H).

LRMS (Electrospray): 559.1 (MH⁻).

EXAMPLE 55

3-{1-(1,3-Benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole##STR83##

The title compound was prepared from the compound of Example 13(a),using the methods of Examples 1(d), 2 and 3, and using4-methylbenzenesulphonamide in place of 4-iosopropylbenzenesulphonamidein the last step.

¹ H NMR (300 MHz, CDCl₃): δ=2.40 (s, 3H), 3.70 (s, 3H), 4.90 (s, 1H),5.90 (s, 2H), 6.60 (s, 1H), 6.65 (d, 1H), 6.70 (d, 1H), 6.75 (s, 1H),6.90 (d, 1H), 7.05 (d, 1H), 7.20 (d, 2H), 7.40 (s, 1H), 7.80 (d, 2H),8.20 (brs, 1H).

EXAMPLE 56

3-{1-(1,3-Benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H)-indole##STR84##

The title compound was prepared from the compound of Example 13(a),using the methods of Examples 1(d), 2 and 3.

¹ H NMR (300 MHz, d₆ -DMSO): δ=1.20 (d, 6H), 3.00 (m, 1H), 3.60 (s, 3H),5.00 (s, 1H), 5.90 (s, 2H), 6.70 (m, 3H), 6.85 (s, 1H), 6.95 (d, 1H),7.00 (d, 1H), 7.40 (d, 2H), 7.60 (s, 1H), 7.75 (d, 2H).

LRMS (APCI): 568.9, 571.2 (MH⁻).

Analysis: found C, 54,82; H, 4.39; N, 4.53; C₂₇ H₂₅ N₂ O₅ SBr.H₂ Orequires C, 55.20; H, 4.63; N, 4.77.

EXAMPLE 57

Ethyl(E)-3-[3-{1-(1,3-benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-methyl-1H-indolyl]-2-propenoate##STR85##

Palladium acetate (9.5 mg, 0.042 mmol) was added to a stirred solutionof3-{1-(1,3-benzodioxol-5-yl)-2-[(2-isopropylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole(the product of Example 56, 200 mg, 0.35 mmol), ethyl acrylate (0.048ml, 0.44 mmol), triethylamine (0.146 ml, 1 mmol) andtri-o-tolylphosphine (32 mg, 0.1 mmol) in acetonitrile (10 ml) at roomtemperature under a nitrogen atmosphere. The solution was heated atreflux for 2 h. After cooling the mixture was poured into brine (50 ml)and extracted with ethyl acetate (2×50 ml). The organic layers werewashed with water (50 ml), dried (MgSO₄) and concentrated to give a greyfoam. Purification by flash column chromatography (elution with 95%dichloromethane /5% methanol) gave the product as a pale yellow foam.

¹ H NMR (400 MHz, CDCl₃): δ=1.30 (d, 6H), 1.35 (t, 3H), 3.00 (m, 1H),3.75 (s, 3H), 4.30 (q, 2H), 5.00 (s, 1H), 5.95 (s, 2H), 6.40 (d, 1H),6.70 (m, 3H), 6.90 (s, 1H), 7.10 (d, 1H), 7.20 (d, 1H), 7.35 (d, 2H),7.40 (s, 1H), 7.80 (d, 1H), 7.85 (d, 2H), 8.20 (brs, 1H).

LRMS (Thermospray): 589.5 (MH⁺).

EXAMPLE 58

(E)-3-[3-{1-(1,3-Benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-6-indolyl]-2-propenoicacid ##STR86##

Ethyl(E)-3-(3-1-(1,3-benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl-1-methyl-1H-6-indolyl)-2-propenoate(the product of Example 57, 120 mg, 0.2 mmol) was dissolved in a 1:1mixture of tetrahydrofuran and methanol (5 ml). Sodium hydroxidesolution (0.6 ml of 1N NaOH) was added and the mixture was heated toreflux with stirring. After 3 h the solvent was removed in vacuo and theproduct was extracted from 1N hydrochloric acid (50 ml) with ethylacetate (2×50 ml). The organic layers were dried (MgSO₄) andconcentrated. Purification by flash column chromatography (gradientelution from 100% dichloromethane to 90% dichloromethane /10% methanol/1% acetic acid) gave the product as a pale green foam (90 mg).

¹ H NMR (300 MHz, CDCl₃): δ=1.30 (d, 6H), 3.00 (m, 1H), 3.80 (s, 3H),5.00 (s, 1H), 5.95 (s, 2H), 6.40 (d, 1H), 6.65 (m, 3H), 6.90 (s, 1H),7.20 (m, 3H), 7.35 (d, 2H), 7.40 (s, 1H), 7.80 (d, 1H), 7.90 (d, 2H).

LRMS (Thermospray): 578.0 (MNH₄ ⁺).

EXAMPLE 59

3-[3-{1-(1,3-Benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-6-indolyl]propanoicacid ##STR87##

10% Palladium-on-carbon (10 mg) was added to a stirred solution of(E)-2-[3-{1-(1,3-benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-6-indolyl]-2-propenoicacid (the compound of Example 58, 80 mg, 0.14 mmol) and ammonium formate(64 mg, 0.5 mmol) in a 1:1 mixture of tetrahydrofuran and ethanol (10 mltotal). The mixture was stirred at reflux for 48 h, cooled, filteredthrough Arbocel™ and concentrated. The grey foam was purified by flashcolumn chromatography (elution with 98% dichloromethane /2% methanol)giving the product as a white foam.

¹ H NMR (300 MHz, CDCl₃): δ=1.25 (d, 6H), 2.70 (t, 2H), 3.00 (m, 3H),3.60 (s, 3H), 4.95 (s, 1H), 5.90 (s, 2H), 6.60 (m, 4H), 6.80 (d, 1H),7.00 (d, 1H), 7.10 (s, 1H), 7.40 (d, 2H), 7.80 (d, 2H), 8.20 (brs, 1H).

LRMS (Thermospray): 563.6 (MH⁺).

EXAMPLE 60

3-{1-(1,3-Benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-6-(4H-1,2,4-triazol-3-yl)-1H-indole##STR88##

Dimethylformamide dimethylacetal (10 ml) was added to3-{1-(1,3-benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-6-indolecarboxamide(the compound of Example 28, 180 mg, 0.36 mmol) and the slurry washeated at reflux for 48 h. The solvent was removed in vacuo and theresidue redissolved in glacial acetic acid (8 ml). Hydrazine hydrate (12mg, 4.68 mmol) was added and the solution heated at reflux for 24 h.After cooling the crude product was extracted from brine (50 ml) withethyl acetate (2×50 ml). The organic layers were dried (MgSO₄) andconcentrated. Flash column chromatography (elution with 96%dichloromethane /4% methanol) gave the desired product as a pale yellowsolid.

¹ H NMR (300 MHz, CDCl₃): δ=2.40 (s, 3H), 2.55 (s, 3H), 5.00 (s, 1H),5.80 (s, 2H), 5.90 (brs, 1H), 6.60 (s, 3H), 6.80 (s, 1H), 7.00 (d, 1H),7.20 (d, 2H), 7.45 (d, 1H), 7.80 (d, 2H), 7.90 (s, 1H), 8.20 (s, 1H).

LRMS (APCI): 530.0 (MH⁻).

EXAMPLE 61

2-(1,3-Benzodioxol-5-yl)-2-[1-methyl-6-(triisopropylsilyloxymethyl)-1H-3-indolyl]aceticacid

(a) 6-Hydroxymethyl-1-methylindole ##STR89##

To a solution of 6-methoxycarbonyl-1-methylindole (prepared by themethod of Example 1(b), but using 6-bromo-1-methylindole in place of6-bromo-1-ethylindole, 5 g) in tetrahydrofuran (30 ml) at -70° C. undera nitrogen atmosphere, was added diisobutyl aluminium hydride (66 ml ofa 1.0M solution in tetrahydrofuran) dropwise with stirring. The solutionwas stirred at -70° C. for 15 mins then warmed to room temperature for 2hours. The mixture was diluted with water (100 ml) and partitionedbetween ethyl acetate and aqueous sodium hydroxide. The aqueous layerwas re-extracted with ethyl acetate and combined organic extracts weredried (MgSO₄) and evaporated to give crude product which was purified byflash column chromatography using 80% ethyl acetate /20% hexane eluantto give the subtitle compound as a clear oil which solidified onstanding (4.1 g).

¹ H NMR (400 MHz, CDCl₃): δ=1.60 (s, 1H), 3.80 (s, 3H), 4.80 (d, 2H),6.45 (s, 1H), 7.00 (s, 1H), 7.05 (d, 1H), 7.35 (s, 1H), 7.60 (d, 1H).

LRMS (Thermospray): 162.3 (MH⁺).

(b) Methyl 2-(1,3-benzodioxol-5-yl)-2-hydroxyacetate ##STR90##

Lithium chloride (11.8 g), potassium hydroxide (31.4 g) andtetrabutylammonium bromide (4.5 g) were dissolved in a mixture of1.4-dioxane (120 ml) and water (120 ml). Piperonal (21 g, 140 mmol) wasadded to this vigorously stirred ice-cold mixture, and after 10 minutesbromoform (12.2 ml 140 mmol) was added dropwise over ˜30 minutes.Stirring was continued for 20 hours at ambient temperature. Water (500ml) was added and the mixture warmed to dissolve the precipitate. Afterwashing with diethylether, the aqueous solution was acidified withconcentrated hydrochloric acid. The crude carboxylic acid intermediatewas isolated by extracted with diethylether and evaporation in vacuo.The residue was dissolved in methanol (500 ml) and acidified with 20drops of concentrated sulphuric acid. The solution was heated to refluxfor 2 hours, then cooled and evaporated in vacuo. The residue wasdissolved in diethylether and washed with water. The organic fractionwas dried (magnesium sulphate), and concentrated in vacuo. Flashchromatography using dichloromethane as eluant, and thenrecrystallisation from diisopropylether gave 13.2 g of the subtitlecompound (m.p. 93-95° C.)

¹ H NMR (300 MHz, CDCl₃): δ=3.35 (d, 1H exchangeable), 3.77 (s, 3H, 5.07(d, 1H), 5.95 (s, 2H), 6.80 (d, 1H), 6.90 (s, 1H), 6.92 (d, 1H).

LRMS (Thermospray): 228.5 (MNH₄ ⁻)

(c) Methyl-2-(1,3-benzodioxol-5-yl)-2-bromoacetate ##STR91##

Hydrobromic acid (20 ml of 62%w/v solution in water) was added to methyl2-(1,3-benzodioxol-5-yl)-2-hydroxyacetate (from step (b). 11 g, 52 mmol)in toluene (200 ml). After stirring for 3 hours the aqueous layer wasremoved and the organic layer was evaporated in vacuo. The residue wasflash chromatographed, eluting with dichloromethane, and thencrystallised with diisopropylether and hexane.

¹ H NMR (300 MHz, CDCl₃): δ=3.76 (s, 3H), 5.26 (s, 1H), 5.95 (s, 2H),6.70 (d, 1H), 6.92 (d, 1H), 7.09 (s, 1H).

m.p.: 39-41° C.

(d) Methyl2-(1,3-benzodioxol-5-yl)-2-[6-(hydroxymethyl)-1-methyl-1H-3-indolyl]acetat##STR92##

2,6-Dimethylpyridine (0.12 ml) was added to a stirred solution of methyl2-(1,3-benzodioxol-5-yl)-2-bromoacetate (from step (c), 273 mg, 1 mmol)and 6-(hydroxymethyl)-1-methylindole (from step (a), 161 mg, 1 mmol) inanhydrous dimethylformamide (2 ml) at ambient temperature under anitrogen atmosphere. The solution was heated to 80° C. for 3 hours. Thereaction mixture was cooled, and partitioned between diethylether andwater, separated and the organic layer dried (magnesium sulphate) andevaporated in vacuo. The residue was flash column chromatography (usingdiethyl as eluant) to give the subtitle compound as a colourless foam(273 mg).

¹ H NMR (300 MHz, CDCl₃): δ=1.64 (t, 1H exchangeable), 3.72 (s, 3H),3.76 (s, 3H), 4.79 (d, 2H), 5.16 (s, 1H), 5.90 (s, 2H), 6.73 (d, 1H),6.85 (d, 1H), 6.90 (s, 1H), 7.03 (d, 1H), 7.08 (s, 1H), 7.31 (s, 1H),7.40 (d, 1H).

LRMS (Thermospray): 353.9 (MH⁺)

(e) Methyl2-(1,3-benzodioxole-5-yl-2-[1-methyl-6-(triisopropylsilyloxymethyl)-1H-3-indolyl]acetate##STR93##

Chlorotriisopropylsilane (0.19 ml, 0.88 mmol) was added to a solution ofmethyl2-(1,3-benzodioxol-5-yl)-2-[6-(hydroxymethyl)-1-methyl-1H-3-indolyl]acetate(from step (d), 260 mg, 0.74 mmol) and imidazole (100 mg, 1.47 mmol) inanhydrous dimethylformamide (3 ml). After 3 hours the mixture waspartitioned between diethyl ether and water, the organic layer wasseparated and washed with water. The organic layer was dried (magnesiumsulphate), and the solvent removed in vacuo. The residue was flashchromatographed (using 50% dichloromethane, 50% hexane as eluent) togive the subtitle compound (305 mg) as an oil.

¹ H NMR (300 MHz, CDCl₃): δ=1.00-1.20 (m, 21H), 3.74 (s, 3H), 3.75 (s,3H), 4.95 (s, 2H), 5.15 (s, 1H), 5.90 (d, 2H), 6.72 (d, 1H), 6.88 (d,1H), 6.91 (s, 1H), 7.00 (d, 1H), 7.03 (s, 1H), 7.34 (s, 1H), 7.36 (d,1H).

LRMS (Thermospray): 510.4 (MH⁺).

(f)2-(1,3-Benzodioxol-5-yl)-2-[1-methyl-6-(triisopropylsilyloxymethyl)-1H-3-indolyl]aceticacid ##STR94##

The subtitle compound was prepared by the method of Example 2 from thecompound of step (e).

¹ H NMR (300 MHz, CDCl₃): δ=1.03-1.22 (m, 21H), 3.72 (s, 3H), 4.96 (s,2H), 5.18 (s, 1H), 5.91 (s, 2H), 6.72 (d, 1H), 6.88 (d, 1H), 6.90 (s,1H), 7.00 (d, 1H), 7.06 (s, 1H), 7.36 (s, 1H), 7.37 (s, 1H).

LRMS (Thermospray): 497.1 (MH⁺)

(g)3-{1-(1,3-Benzodioxol-5-yl)-2-[(2-ethyl-4-methylphenyl)sulfonamido]-2-oxoethyl}-6-(triisopropylsilyloxymethyl)-1-methyl-1H-indole##STR95##

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113 mg,0.59 mmol) was added to a stirred solution of2-(1,3-benzodioxol-5-yl)-2-[6-(triisopropylsilyloxymethyl)-1-methyl-1H-3-indolyl]aceticacid (from step (f), 250 mg, 0.49 mmol), N,N-dimethylaminopyridine (78mg, 0.64 mmol) and the sulphonamide from Preparation 1 (107 mg, 0.54mmol) in dichloromethane (6 ml) at room temperature under a nitrogenatmosphere. After 12 h the reaction mixture was poured into 1Nhydrochloric acid (50 ml) and extracted with dichloromethane (2×50 ml).The organic fraction were dried (MgSO₄) and concentration to give ayellow foam. Flash column chromatography (elution with 98%dichloromethane /2% methanol) gave the subtitle (95 mg) as a white foam.

¹ H NMR (400 MHz, CDCl₃): δ=1.00 (t, 3H), 1.10 (d, 18H), 1.15 (m, 3H),2.35 (s, 3H), 2.50 (q, 2H), 3.60 (s, 3H), 4.90 (s, 2H), 4.95 (s, 1H),5.80 (s, 2H), 6.65 (m, 3H), 6.70 (s, 1H), 6.90 (d, 1H), 7.05 (s, 1H),7.10 (m, 2H), 7.35 (s, 1H), 8.00 (d, 1H).

LRMS (Thermospray): 677.4 (MH⁺).

(h)3-{1-(1,3-Benzodioxole-5-yl)-2-[(2-ethyl-4-methylphenyl)sulfonamido]-2-oxoethyl}-6-(hydroxymethyl)-1-methyl-1H-indole##STR96##

Tetraethylammonium fluoride (312 mg, 2.18 mmol) was added to a stirredsolution of the compound of step (g) (380 mg, 0.55 mmol) in acetonitrile(6 ml) at room temperature under a nitrogen atmosphere. After 12 h themixture was poured into 1M hydrochloric acid (50 ml) and extracted intoethyl acetate (2×50 ml). The organic fractions were combined, dried(MgSO₄) and concentrated in vacuo to give a yellow foam. Flash columnchromatography (eluting with 98% dichloromethane /2% methanol) gave theproduct as a white solid (242 mg).

¹ H NMR (400 MHz, CDCl₃): δ=1.15 (t, 2H), 2.30 (s, 3H), 2.60 (q, 2H);3.60 (s, 3H), 4.75 (s, 2H), 5.25 (s, 1H), 5.80 (s, 2H), 6.60 (m, 3H),6.80 (s, 1H), 6.95 (d, 1H), 7.05 (s, 1H), 7.10 (d, 2H), 7.20 (s, 1H),8.00 (s, 1H).

LRMS (Thermospray): 538.2 (MNH₄ ⁻).

Examples 62-64 were prepared by the methods of Example 61, but using theappropriate sulphonamide in the penultimate step.

    __________________________________________________________________________      #STR97##                                                                      #STR98##                                                                    Example                                                                         N.sup.0 Ar Physical Data                                                    __________________________________________________________________________      62(a)*                                                                                             #STR99##                                                                    .sup.1 H NMR (300 MHz, CDCl.sub.3): δ = 1.05                            (d, 18H), 1.20  (m, 3H), 2.40 (s, 3H), 3.75 (s, 3H),                          4.95 (s, 3H), 5.95  (s, 2H), 6.70 (d, 2H), 6.75 (s,                           1H), 6.80 (s, 1H), 6.90  (d, 1H), 7.00 (d, 1H), 7.10                          (d, 1H), 7.20 (d, 1H), 7.40  (s, 1H), 7.90 (t, 1H),                           8.25 (s, 1H).  LRMS (APCI): 668.0 (MH.sup.+).                                   - 62(b)                                                                       .sup.1 H NMR (400 MHz, d.sub.6 -DMSO): δ =                            2.30 (s, 3H), 3.60  (s, 3H), 4.50 (s, 2H), 5.00                               (brs, 1H), 5.10 (s, 1H), 5.90  (s, 2H), 6.60 (s,                              1H), 6.65 (d, 1H), 6.80 (d, 1H), 6.85  (s, 1H), 6.90                          (d, 1H), 7.10 (d, 1H), 7.15 (d, 1H), 7.20  (d, 1H),                           7.25 (s, 1H), 7.50 (s, 1H), 7.70 (t, 1H), 12.50  (s,                          1H).  LRMS (Thermospray): 511.2 (MH.sup.+).                 - 63(a)                                                                                           .sup.1 H NMR (400 MHz, CDCl.sub.3): δ = 1.10                          (d, 18H), 1.15  (m, 3H), 3.40 (s, 3H), 3.65 (s, 3H),                          4.45 (s, 2H), 4.90  (s, 3H), 5.90 (s, 2H), 6.60 (m,                           3H), 6.90 (d, 1H), 7.00  (d, 1H), 7.30 (s, 1H), 7.40                          (d, 2H), 7.85 (d, 2H), 8.05  (s, 1H).  LRMS (APCI):                           681.6 (MH.sup.+).                                           - 63(b)                                                                                           .sup.1 H NMR (400 MHz, d.sub.6 -DMSO): δ =                            3.25 (s, 3H), 3.60  (s, 3H), 4.45 (s, 2H), 4.50 (m,                           2H), 5.00 (brs, 1H), 5.05  (s, 1H), 5.80 (s, 2H),                             6.60 (s, 1H), 6.65 (d, 1H), 6.75  (d, 2H), 6.85 (d,                           1H), 7.00 (d, 1H), 7.25 (s, 1H), 7.40  (d, 2H), 7.80                          (d, 2H), 12.4 (brs, 1H).  LRMS (Thermospray): 523.4                           (MH.sup.+).                                                 - 64(a)                                                                                           .sup.1 H NMR (400 MHz, CDCl.sub.3): δ = 1.05                          (d, 18H), 1.20  (m, 3H), 3.60 (s, 3H), 3.80 (s, 3H),                          4.60 (s, 2H), 4.90  (s, 3H), 5.85 (s, 2H), 6.60 (m,                           4H), 6.90 (d, 3H), 7.00  (d, 1H), 7.35 (s, 1H), 7.80                          (d, 2H), 8.10 (brs, 1H).  LRMS (APCI): 723.0                                  (MH.sup.+).                                                 - 64(b)                                                                                           .sup.1 H NMR (400 MHz, CDCl.sub.3): δ = 2.00                          (brs, 1H), 3.60  (s, 3H), 3.75 (s, 3H), 4.60 (s,                              2H), 4.70 (s, 2H), 5.00 (s,  1H), 5.80 (s, 2H), 6.60                          (d, 1H), 6.70 (d, 1H), 6.75 (s,  1H), 6.80 (s, 1H),                           6.85 (d, 2H), 6.90 (d, 1H), 7.10 (d,  1H), 7.20 (s,                           1H), 7.80 (d, 2H).  LRMS (APCI): 567 (MH.sup.+).         __________________________________________________________________________     * See Preparation 2 for sulphonamide preparation                         

EXAMPLE 65

3-{1-(1,3-Benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-6-(hydroxymethyl)-1-methyl-1H-indole

(a)3-{1-(1,3-Benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}06-(methoxycarbonyl)-1-methyl-1H-indole

The subtitle compound was prepared using the methods of Examples 1(b),1(d), 2 and 3, but starting with 6-bromo-1-methylindole in place6-bromo-1-ethylindole, and reacting with the sulphonamide of Preparation11 in the method of Example 3.

(b)3-{1-(1,3-Benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-6-(hydroxymethyl)-1-methyl-1H-indole##STR105##

Lithium aluminium hydride (15 mg, 0.2 mmol) was added slowly to astirred solution of methyl3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxo-ethyl}-1-methyl-1H-6-indolecarboxyate(from step (a), 200 mg, 0.4 mmol) in tetrahydrofuran at 0° C. under anitrogen atmosphere. After 2 h a further 1 equivalent (30 mg) of lithiumaluminium hydride was added and the mixture was warmed to roomtemperature. After 1 h ethyl acetate (10 ml) was carefully added and theproduct extracted from 1N hydrochloric acid with ethyl acetate (2×50ml). The combined organic layers were dried (MgSO₄) and concentrated invacuo. Purification by flash column chromatography (elution with 95%dichloromethane /5% methanol) gave the product as a white solid (130mg).

¹ H NMR (400 MHz, CD₃ OD): δ=2.45 (s, 3H), 3.55 (s, 3H), 3.75 (s, 3H),4.75 (s, 2H), 5.15 (s, 1H), 5.95 (d, 2H), 6.70 (s, 1H), 6.75 (m, 3H),6.85 (s, 1H), 6.95 (d, 1H), 7.00 (d, 1H), 7.25 (d, 1H), 7.35 (s, 1H),7.85 (d, 1H).

LRMS (Thermospray): 523.7 (MH⁺).

Analysis: Found: C, 61.00; H, 5.12; N, 5.19

C₂₇ H₂₆ N₂ O₇ S.0.5H₂ O; Requires: C, 61.00; H, 5.12; N, 5.27.

m.p.=184-186° C.

The title compound was separated into its individual enantiomers using aChiralpak™ AD column (25×2 cm) with a flow rate of 10 ml/min using a70:30 mix of hexane:iso-propylalcohol with 0.6% trifluoroacetic acid and0.4% diethylamine added. The products were detected at 220 nm and hadretention times of 32 min and 39 min.

The enantiomeric purity was checked by chromatographing 100 μl of theeluent from the above separation, using a Chiralpak™ AD column (25×0.46cm), a flow rate of 1 ml/min and a 70:30 mix of hexane:iso-propylalcoholwith 0.3% trifluoroacetic acid and 0.2% diethylamine added as eluant.The products were detected at 220 nm and had retention times of 15.5 minand 18 min.

Examples 66 and 67 were prepared by the method of Example 65, but usingthe sulphonamides of Preparations 10 and 9 respectively.

    __________________________________________________________________________      #STR106##                                                                   Example                                                                         N.sup.0 Ar Physical Data                                                    __________________________________________________________________________      66                                                                                              #STR107##                                                                   .sup.1 H NMR (300 MHz CDCl.sub.3): 2.40 (s, 3H), 3.25                         (s, 3H),  3.40-4.00 (m, 2H), 3.70 (s, 3H) 4.80 (d, 2H),                       5.05 (s,  1H), 5.90 (s, 2H), 5.60-7.40 (m, 9H), 7.90                          (d, 2H),  9.00 (s, 1H).  LRMS (Thermospray): 567.1                            (MH.sup.-).                                                    - 67                                                                                           .sup.1 H NMR (400 MHz d.sub.6 -DMSO): 1.10 (t, 3H),                         2.30 (d,  2H), 3.60 (s, 3H), 3.70-3.90 (m, 2H), 4.50                          (d, 2H),  5.00 (t, 1H), 5.15 (s, 1H), 5.90 (d, 2H),                           6.60-7.65 (m,  10H), 12.05 (s, 0.5H), 12.30 (s, 0.5H).                        LRMS (Thermospray): 537.4 (MH.sup.-).                       __________________________________________________________________________

EXAMPLE 68

2-(1,3-Benzodioxol-5-yl)-2-(5-bromo-1-methyl-1H-3-indolyl)acetic acid

(a) 5-Bromo-1-methylindole ##STR109##

Sodium hydride (440 mg of a 60% dispersion in paraffin wax) was added toa stirred solution of 5-bromoindole (1.96 g, 10 mmol) indimethylformamide (20 ml) at ambient temperature under a nitrogenatmosphere. After 30 minutes methyl p-toluenesulphonate (2.05 g 11 mmol)was added. After 20 hours the mixture was partitioned between diethylether and water. The organic layer was separated and washed twice withwater. The organic layer was dried (magnesium sulphate) and the solventwas removed in vacuo. The residue was purified by flash columnchromatography (using 50% hexane, 50% dichloromethane as eluant) to give2.07 g of product as a waxy solid.

¹ H NMR (300 MHz, CDCl₃): δ=3.75 (s, 3H), 6.42 (d, 1H), 7.05 (d, 1H),7.17 (d, 1H), 7.28 (d, 1H), 7.75 (s, 1H).

LRMS (Thermospray): 212 (MH⁺)

(b)Methyl-2-(1,3-benzodioxol-5-yl)-2-(5-bromo-1-methyl-1H-3-indolyl)acetate##STR110##

2.6-Dimethylpyridine (0.75 ml) was added to a stirred solution of methyl2-(1,3-benzodioxol-5-yl)-2-bromoacetate (from Example 61(c), 1.75 g,6.43 mmol) and 5-bromo-1-methylindole (from step (a), 1.35 g) inanhydrous dimethylformamide (10 ml) at ambient temperature, under anitrogen atmosphere. The solution was heated to 80° C. for 8 hours. Thereaction mixture was partitioned between diethylether and water,separated and the organic layer dried (magnesium sulphate) andevaporated in vacuo. The residue was flash chromatographed (using 50%dichloromethane and 50% hexane as eluant) to give the subtitle compoundas a colourless oil (1.98 g).

¹ H NMR (300 MHz, CDCl₃): δ=3.72 (s, 3H), 3.74 (s, 2H), 6.75 (d, 1H),6.85 (d, 1H), 6.88 (s, 1H), 7.10 (s, 1H), 7.15 (d, 1H), 7.28 (d, 1H),7.55 (s, 1H).

LRMS (Thermospray): 402.2, 404.0 (MH⁻).

(c) 2-(1,3-Benzodioxol-5-yl)-2-(5-bromo-1-methyl)-1H-3-indolyl)aceticacid ##STR111##

Aqueous sodium hydroxide (14.7 ml of 1M) was added to a solution ofmethyl 2-(1,3-benzodioxol-5-yl)-2-(5-bromo-1-methyl-1H-3-indolyl)acetatefrom (b) (1.97 g, 4.9 mmol) in a 3:1 mixture of methanol and 1,4-dioxaneat ambient temperature. The mixture was heated to reflux for 1 hourbefore recooling and removing the organic solvents in vacuo. The residuewas redissolved in water and acidified with drops of concentratedhydrochloric acid. The resultant precipitate was extracted withdiethylether, dried (magnesium sulphate) and the solvent removed invacuo. The residue was crystallised from diisopropylether to give thesubtitle compound (1.59 g).

¹ H NMR (300 MHz, CDCl₃): δ=3.74 (s, 3H), 5.09 (s, 1H), 5.92 (s, 2H),6.75 (d, 1H), 6.85 (d, 1H), 6.88 (s, 1H), 7.10 (s, 1H), 7.15 (d, 1H),7.28 (d, 1H), 7.55 (s, 1H).

LRMS (Thermospray): 388.4, 390.4 (MH⁺)

Analysis: Found C, 55.61; H, 3.66; N, 3.51.

C₁₈ H₁₄ BrNO₄ requires C, 55.69; H, 3.64; N, 3.60.

m.p.: 191-193° C.

Examples 69-78 were prepared by the method of Example 68, starting withthe appropriately substituted indole.

    __________________________________________________________________________      #STR112##                                                                   Example                                                                            R.sup.1 =                                                                              Data                                                            __________________________________________________________________________    69   5-F      .sup.1 H NMR (300 MHz, CDCl.sub.3) δ = 3.75 (s, 3H),                    5.10 (s,                                                           (C.sub.18 H.sub.14 FNO.sub.4) 1H), 5.92 (s, 2H), 6.74 (d, 1H),                           6.83-7.00 (m, 3H), 7.06                                             (d, 1H), 7.15 (s, 1H), 7.18 (m, 1H)                                           LRMS (Thermospray): 328.2 (MH.sup.-)                                        70 5-NC .sup.1 H NMR (300 MHz, CDCl.sub.3): δ = 3.80 (s, 3H),                       5.15 (s,                                                           (C.sub.19 H.sub.14 N.sub.2 O.sub.4) 1H), 5.94 (s, 2H), 6.76 (d, 1H),                     6.84 (s, 1H), 6.85 (d,                                              1H), 7.26 (s, 1H), 7.32 (d, 1H), 7.42 (d, 1H), 7.75 (s,                       1H).                                                                          LRMS (Thermospray): 352.3 (MH.sup.-)                                        71 5-CH.sub.3 O .sup.1 H NMR (300 MHz, CDCl.sub.3): δ = 3.72 (s,                    3H), 3.78 (s,                                                      (C.sub.19 H.sub.17 NO.sub.5) 3H), 5.13 (s, 1H), 5.92 (s, 2H), 6.77 (d,                   1H), 6.86 (m,                                                       2H), 6.92 (s, 1H), 7.06 (s, 1H), 7.16-7.27 (m, 2H),                           LRMS (Thermospray): 340.4 (MH.sup.+)                                        72 6-F .sup.1 H NMR (300 MHz, CDCl.sub.3): δ = 3.70 (s, 3H), 5.13                   (s,                                                                (C.sub.18 H.sub.14 FNO.sub.4) 1H), 5.92 (s, 2H), 6.70-6.98 (m, 5H),                      7.06 (s, 1H), 7.33                                                  (m, 1H).                                                                      LRMS (Thermospray): 327.8 (MH.sup.+)                                          m.p.: 150-152° C.                                                    73 6-Cl .sup.1 H NMR (300 MHz, d.sub.6 -DMSO): δ = 3.75 (s, 3H),                    5.08                                                               (C.sub.18 H.sub.14 ClNO.sub.4) (s, 1H), 5.95 (s, 2H), 6.80-6.90 (m,                      3H), 6.97 (d, 1H),                                                  7.27 (s, 1H), 7.40 (d, 1H), 7.50 (s, 1H), 12.50 (br, 1H                       exchangeable).                                                                LRMS (Thermospray): 343.9 (MH.sup.+)                                        74 6-Br .sup.1 H NMR (400 MHz, d.sub.6 -DMSO): δ = 3.71 (s, 3H),                    5.03                                                               (C.sub.18 H.sub.14 BrNO.sub.4) (s, 1H), 5.90 (d, 2H), 6.75-6.82 (m,                      2H), 6.84 (s, 1H),                                                  7.06 (d, 1H), 7.22 (s, 1H), 7.32 (d, 1H), 7.61 (s, 1H),                       12.60 (br, 1H exchangeable).                                                  Analysis: Found: C, 55.50: H, 3.60: N, 3.54.                                  C.sub.18 H.sub.14 BrNO.sub.4 Requires: C, 55.69: H, 3.64: N, 3.60.                       75 7-F .sup.1 H NMR (400 MHz, CDCl.sub.3): δ = 3.93                    (s, 3H), 5.10 (s,                                                  (C.sub.18 H.sub.14 FNO.sub.4) 1H), 5.90 (s, 2H), 6.72 (d, 1H),                           6.80-6.93 (m, 4H), 7.02                                             (s, 1H), 7.11 (d, 1H).                                                        LRMS (Thermospray): 328.2 (MH.sup.+)                                        76 7-Cl .sup.1 H NMR (400 MHz, CDCl.sub.3): δ = 4.09 (s, 3H),                       5.10 (s,                                                           (C.sub.18 H.sub.14 ClNO.sub.4) 1H), 5.90 (s, 2H), 6.72 (d, 1H), 6.82                     (d, 1H), 6.83 (s, 1H),                                              6.88 (t, 1H), 7.01 (s, 1H), 7.10 (s, 1H), 7.28 (d, 1H).                       LRMS (Thermospray): 344.2 (MH.sup.+)                                          m.p.: 146-147° C.                                                    77 7-Br .sup.1 H NMR (300 MHz, CDCl.sub.3): δ = 4.10 (s, 3H),                       5.10 (s,                                                           (C.sub.18 H.sub.14 BrNO.sub.4) 1H), 5.90 (s, 2H), 6.71 (d, 1H),                          6.80-6.86 (m, 3H), 7.03                                             (s, 1H), 7.29-7.34 (m, 2H).                                                   LRMS (Thermospray): 388.1 (MH.sup.+)                                          m.p.: 151° C.                                                        78 6-CN .sup.1 H NMR (400 MHz, CDCl.sub.3): δ = 3.80 (s, 3H),                       5.15 (s,                                                           (C.sub.19 H.sub.14 N.sub.2 O.sub.4) 1H), 5.80 (s, 2H), 6.75 (d, 1H),                     6.85 (m, 1H), 7.25 (m,                                              2H), 7.40 (d, 1H), 7.60 (s, 1H).                                              LRMS (Thermospray): (MH.sup.+).                                           __________________________________________________________________________

EXAMPLE 793-{1-(1,3-Benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-5-bromo-1-methyl-1H-indole##STR113##

4-Dimethylaminopyridine (151 mg) was added to a solution of2-(1,3-benzodioxol-5-yl)-2-(5-bromo-1-methyl-1H-3-indolyl) acetic acid(the product of Example 68, 480 mg. 1.24 mmol) in anhydrousdichloromethane (10 ml) at ambient temperature.2-Methoxy-4-methyl-1-benzenesulfonamide (from Preparation 11, 300 mg,1.48 mmol) was added to the solution followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (355 mg,1.85 mmol), and stirring was continued for 20 hours. The solution waswashed twice with 2N hydrochloric acid, and dried (magnesium sulphate)and the solvents removed in vacuo. The residue was flash chromatographedusing 1% methanol in dichloromethane as eluant, and crystallised fromdichloromethane and diethyl ether mixture to give the subtitle compound(535 mg).

¹ H NMR (400 MHz, d₆ -DMSO): δ=2.30 (s, 3H), 3.55 (s, 3H), 3.64 (s, 3H),5.10 (s, 1H), 5.90 (d, 2H), 6.63 (d, 1H), 6.66 (s, 1H), 6.72-7.00 (m,4H), 7.19 (d, 1H), 7.32 (d, 1H), 7.34 (s, 1H), 7.62 (d, 1H), 11.70 (s,1H exchangeable).

LRMS (Thermospray): 588.2 (MNH₄ ⁻).

Analysis: Found C, 53.79; H, 4.29; N, 4.62.

C₂₆ H₂₃ BrN₂ O₆ S; 0.5 H₂ O requires: C, 53.80; H, 4.17; N, 4.83.

m.p. 145-150° C.

Examples 80-88 were prepared by the method of Example 79 using thecarboxylic acids of Examples 69-76 and 78 respectively.

    __________________________________________________________________________      #STR114##                                                                   Example                                                                            R' =     Data                                                            __________________________________________________________________________    80   5-F      .sup.1 H NMR (400 MHz, CDCl.sub.3): δ = 2.37 (s, 3H),                   3.45 (s,                                                           (C.sub.26 H.sub.23 FN.sub.2 O.sub.6 S) 3H), 3.68 (s, 3H), 4.96 (s,                       1H), 5.88 (s, 2H), 6.60 (s,                                         1H), 6.63-6.69 (m, 3H), 6.74-6.96 (m, 4H), 7.15 (m,                           1H), 7.89 (d, 1H), 8.50 (br, 1H exchangeable).                                LRMS (Thermospray): 511.4 (MH.sup.+), 528.1 (MNH.sub.4.sup.-)                            81 5-NC .sup.1 H NMR (300 MHz, CDCl.sub.3): δ = 2.42                   (s, 3H) 3.63 (s,                                                    3H), 3.75 (s, 3H), 5.03 (s, 1H), 5.94 (s, 2H), 6.68 (s,                       1H), 6.70-6.76 (m, 3H), 6.90 (d, 1H), 7.02 (s, 1H),                           7.30 (d, 1H), 7.42 (d, 1H), 7.50 (s, 1H), 7.90 (d, 1H),                       8.38 (brs, 1H exchangeable).                                                  LRMS (Thermospray): 535.0 (MNH.sub.4.sup.-)                                   Analysis: Found: C, 61.54; H, 4.75: N, 7.49.                                  C.sub.27 H.sub.23 N.sub.3 O.sub.6 S: 0.5 H.sub.2 O                            Requires: C, 61.59; H, 4.59; N, 7.98.                                       82 5-CH.sub.3 O .sup.1 H NMR (300 MHz, CDCl.sub.3): δ = 2.40 (s,                    3H), 3.35 (s,                                                       3H), 3.62 (s, 3H), 3.74 (s, 3H), 5.00 (s, 1H), 5.92 (s,                       2H), 6.58 (m, 2H), 6.70-6.78 (m, 3H), 6.80 (s, 1H),                           6.82-6.90 (m, 2H), 7.20 (d, 1H), 7.92 (d, 1H), 8.40                           (brs, 1H exchangeable).                                                       LRMS (Thermospray): 523.0 (MH.sup.+)                                        83 6-F .sup.1 H NMR (400 MHz, CDCl.sub.3): δ = 2.37 (s, 3H), 3.41                   (s,                                                                (C.sub.26 H.sub.23 FN.sub.2 O.sub.6 S) 3H), 3.60 (s, 3H), 4.96 (s,                       1H), 5.88 (s, 2H), 6.55 (s,                                         1H), 6.62-6.70 (m, 4H), 6.81 (s, 1H), 6.80-6.90 (m,                           2H), 7.08 (m, 1H), 7.89 (d, 1H), 8.80 (br, 1H                                 exchangeable).                                                                LRMS (Thermospray): 511.4 (MH.sup.+)                                        84 6-Cl .sup.1 H NMR (300 MHz, d.sub.6 -DMSO): δ = 2.35 (s, 3H),                    3.62                                                               (C.sub.26 H.sub.23 ClN.sub.2 O.sub.6 S) (s, 3H), 3.70 (s, 3H), 5.18                      (s, 1H), 5.92 (s, 2H), 6.68-                                        6.74 (m, 2H), 6.80 (d, 1H), 6.87 (d, 1H), 6.93-7.00 (m,                       3H), 7.20 (d, 1H), 7.50 (s, 1H), 7.67 (d, 1H), 12.25 (s,                      1H exchangeable).                                                             LRMS (Thermospray): 526.9 (MH.sup.+)                                        85 6-Br .sup.1 H NMR (400 MHz, CDCl.sub.3): δ = 2.38 (s, 3H),                       3.40 (s,                                                           (C.sub.26 H.sub.23 BrN.sub.2 O.sub.6 S) 3H), 3.60 (s, 3H), 4.95 (s,                      1H), 5.88 (s, 2H), 6.55 (s,                                         1H), 6.64 (m, 3H), 6.82 (m, 2H), 7.00 (m, 2H), 7.36 (s,                       1H), 7.87 (d, 1H), 8.75 (br, 1H exchangeable).                                LRMS (APCI): 571.8 (MH.sup.+)                                                 Analysis: Found: C, 52.20: H, 3.91: N, 4.62.                                  C.sub.26 H.sub.23 BrN.sub.2 O.sub.6 S: 0.4 CH.sub.2 Cl.sub.2 requires:                   C, 52.38: H,                                                       3.96. N, 4.63.                                                                m.p.: 145-150° C. (dec.),                                            86 7-F .sup.1 H NMR (400 MHz, CDCl.sub.3): δ = 2.38 (s, 3H), 3.47                   (s                                                                 (C.sub.26 H.sub.23 FN.sub.2 O.sub.6 S) 3H), 3.84 (s, 3H), 4.98 (s,                       1H), 5.90 (s, 2H), 6.59 (s,                                         1H), 6.67 (s, 3H), 6.77 (s, 1H), 6.80-6.96 (m, 3H), 6.93                      (m, 1H), 7.88 (d, 1H), 8.50 (br, 1H exchangeable),                            LRMS (Thermospray): 511.2 (MH.sup.+), 528.1 (MNH.sub.4 .sup.+).                            m.p.: 123-124° C.                                       87 7-Cl .sup.1 H NMR (300 MHz, CDCl.sub.3): δ = 2.38 (s, 3H),                       3.47 (s,                                                           (C.sub.26 H.sub.23 ClN.sub.2 O.sub.6 S) 3H), 3.89 (s, 3H), 4.98 (s,                      1H), 5.90 (s, 2H), 6.59 (s,                                         1H), 6.66 (s, 3H), 6.75 (s, 1H), 6.80-6.90 (m, 2H),                           7.03-7.13 (m, 2H), 7.85 (d, 1H), 8.40 (br, 1H                                 exchangeable).                                                                LRMS (APCI): 528.7 (MH.sup.+)                                                 m.p.: 233-234° C.                                                    88 6-CN .sup.1 H NMR (400 MHz, CDCl.sub.3): δ = 2.40 (s, 3H),                       3.50 (s,                                                           (C.sub.27 H.sub.23 N.sub.3 O.sub.6 S) 3H), 3.70 (s, 3H), 5.00 (s, 1H),                   5.90 (s, 2H), 6.60 (d,                                              1H), 6.65 (d, 1H), 6.65 (s, 1H), 6.80 (d, 1H), 7.10 (s,                       1H), 7.15 (d, 1H), 7.20 (s, 1H), 7.25 (d, 1H), 7.55 (s,                       1H), 7.85 (d, 1H), 8.70 (s, 1H).                                              LRMS (APCI): 517.8 (MH.sup.+).                                            __________________________________________________________________________

EXAMPLE 89

Ethyl2-(4-[2-(1,3-benzodioxol-5-yl)-2-(6-chloro-1-methyl-1H-3-indolyl)acetyl]-sulfamoylphenyl)acetate##STR115##

The title compound was prepared by the method of Example 79 from thecompound of Example 73 and the appropriate sulphonamide.

¹ H NMR (400 MHz, CDCl₃): δ=1.15 (t, 3H), 3.60 (s, 3H), 3.80 (s, 2H),4.00 (q, 2H), 5.00 (s, 1H), 5.85 (s, 2H), 6.60 (m, 2H), 6.75 (d, 1H),6.85 (s, 1H), 6.90 (d, 1H), 7.05 (d, 1H), 7.40 (d, 2H), 7.45 (s, 1H),7.80 (d, 2H). LRMS (Thermospray): 585.9, 588.6 (MNH₄ ⁻).

Example 903-[1-(1,3-Benzodioxol-5-yl)-2-[4-(2-hydroxyethyl)phenyl]sulfonamido-2-oxoethyl]-6-chloro-1-methyl-1H-indole##STR116##

Lithium aluminium hydride (6 mg, 0.16 mmol) was added to a stirredsolution of ethyl2-(4-[2-(1,3-benzodioxol-5-yl)-2-(6-chloro-1-methyl-1H-3-indolyl)acetyl]sulfamoylphenyl)acetate(the product of Example 89, 80 mg, 0.14 mmol) in tetrahydrofuran (6 ml)at 0° C. under a nitrogen atmosphere. After 40 mins ethyl acetate (1 ml)was slowly added and the reaction mixture was poured into hydrochloricacid (50 ml). The product was extracted into ethyl acetate (2×50 ml),dried (MgSO₄) and concentrated. Recrystallisation (methanol/ether) gavethe product as a white crystalline solid (50 mg).

¹ H NMR (400 MHz, d₆ -DMSO): δ=2.80 (t, 2H), 3.60 (t, 2H), 3.65 (s, 3H),4.60 (brs, 1H), 5.00 (s, 1H), 5.95 (s, 2H), 6.65 (d, 1H), 6.70 (s, 1H),6.80 (d, 1H), 6.90 (s, 1H), 6.95 (d, 1H), 7.10 (d, 1H), 7.40 (d, 2H),7.45 (s, 1H), 7.75 (d, 2H). LRMS (Thermospray): 544.0, 545.7 (MNH₄ ⁺).

Example 913-(1-(1,3-Benzodioxol-5-yl)-2-[4-(2-hydroxyethoxy)phenyl]sulfonamido-2-oxoethyl)-6-hydroxymethyl-1-methyl-1H-indole##STR117##

The title compound was prepared by the method of Example 90 from thecompound of Example 64(g).

¹ H NMR (400 MHz, CDCl₃): δ=3.50 (s, 3H), 3.60 (t, 1H), 3.80 (m, 2H),3.90 (t, 1H), 3.95 (m, 2H), 4.55 (d, 2H), 4.95 (s, 1H), 5.70 (s, 2H),6.50 (d, 1H), 5.95 (s, 1H), 6.60 (d, 1H), 6.65 (d, 1H), 6.80 (d, 3H),6.90 (d, 1H), 7.10 (s, 1H), 7.70 (d, 2H). LRMS (APCI): 540.0 (MH⁺).

Example 926-Bromo-3-{1-(7-methoxy-1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-indole

(a) Methyl 2-hydroxy-2-(7-methoxy-1,3-benzodioxol-5-yl)acetate##STR118##

The substitute compound was prepared using the method of Example 61(b)from 7-methoxy-1,3-benzodioxole-5-carbaldehyde (12.6 g) as a waxy solid(4.5 g).

¹ H NMR (300 MHz, CDCl₃): δ=3.40 (d, 1H exchangeable), 3.76 (s, 3H),3.90 (s, 3H), 5.06 (d, 1H), 5.97 (s, 2H), 6.59 (s, 1H), 6.61 (s, 1H).LRMS (Thermospray): 258 (MNH₄ ⁻).

(b) Methyl 2-bromo-2-(7-methoxy-1,3-benzodioxol-5-yl)acetate ##STR119##

The subtitle compound was prepared from methyl2-hydroxy-2-(7-methoxy-1,3-benzodioxol-5-yl)acetate (the product of step(a), 4.45 g, 19 mmol) by the method of Example 61(c) (yield 2.25 g).

¹ H NMR (300 MHz, CDCl₃): δ=3.80 (s, 3H), 3.92 (s, 3H), 5.25 (s, 1H),5.98 (s, 2H), 6.73 (s, 1H), 6.78 (s, 1H).

(c) Methyl2-(6-bromo-1H-3-indolyl)-2-(7-methoxy-1,3-benzodioxol-5-yl)acetate##STR120##

Methyl magnesium bromide (3.6 ml of 3M solution in diethyl ether) wasadded dropwise to a stirred solution of 6-bromo-indole (2.13 g, 10.9mmol) in toluene (20 ml) under a nitrogen atmosphere. After 20 minutesthe reaction mixture was transferred via a cannula, over ˜10 minutes, toa stirred solution of methyl2-bromo-2-(7-methoxy-1,3-benzodioxol-5-yl)acetate (from step (b), 2.2 g,7.26 mmol) in toluene (20 ml) at ambient temperature. After a further 2hours the mixture was poured into a mixture of diethyl ether and aqueousammonium chloride. The organic layer was separated and dried (magnesiumsulphate), and the solvent was removed in vacuo. The residue was flashchromatographed using dichloromethane as eluent to give the subtitlecompound (2.7 g).

¹ H NMR (300 MHz, CDCl₃): δ=3.72 (s, 3H), 3.83 (s, 3H), 5.08 (s, 1H),5.92 (s, 2H), 6.58 (s, 2H), 7.10-7.30 (m, 3H), 7.50 (s, 1H), 8.1 (br,1H). LRMS (Thermospray): 420.1 (MH⁻).

(d) Methyl2-(6-bromo-1-methyl-1H-3-indolyl)-2-(7-methoxy-1,3-benzodioxol-5-yl)acetat##STR121##

Sodium hydride (289 mg of a 60% dispersion in paraffin wax) was added inportions to a stirred solution of methyl2-(6-bromo-1H-indolyl)-2-(7-methoxy-1,3-benzodioxol-5-yl)acetate (fromstep (c), 2.7 g, 6.5 mmol) in anhydrous dimethylformamide (20 ml) at 0°C. under a nitrogen atmosphere. After 30 minutes, methylp-toluenesulphonate (1.34 g, 7.2 mmol) was added. After a further 1 hourthe mixture was partitioned between diethyl ether and water. The organiclayer was separated and washed twice with water. The organic layer wasdried (magnesium sulphate) and the solvent was removed in vacuo. Theresidue was purified by flash column chromatography (using 30% hexane,70% dichloromethane as eluant) to give 1.49 g of the subtitle compound.

¹ H NMR (300 MHz, CDCl₃): δ=3.72 (s, 3H), 3.75 (s, 3H), 3.85 (s, 3H),5.08 (s, 1H), 5.92 (s, 2H), 3.78 (s, 2H), 7.04 (s, 1H), 7.17 (d, 1H),7.28 (s, 1H), 7.43 (s, 1H). LRMS (Thermospray): 432.2 (MH⁻).

(e)6-bromo-3-{1-(7-methoxy-1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-indole##STR122##

The title compound was prepared from the product of step (d) using themethods of Examples 68(c) and 79.

¹ H NMR (300 MHz, d₆ -DMSO): δ=2.36 (s, 3H), 3.60 (s, 3H), 3.69 (s, 3H),3.72 (s, 3H), 5.12 (s, 1H), 5.95 (s, 2H), 6.39 (s, 1H), 6.45 (s, 1H),6.88 (d, 1H), 6.95 (s, 2H), 7.07 (d, 1H), 7.17 (d, 1H), 7.62 (s, 1H),7.64 (d, 1H), 12.20 (s, 1 H exchangeable). LRMS (APCI): 602.9 (MH⁺).Analysis: Found: C, 53.47; H, 4.11; N, 4.62. C₂₇ H₂₅ BrN₂ O₇ S;requires: C, 53.91; H, 4.19; N, 4.66. m.p.: 235° C. (dec.) frommethanol.

Example 936-Bromo-3-{1-(6-chloro-1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-indole

(a) Methyl 2-(6-chloro-1,3-benzodioxol-5-yl)-2-hydroxyacetate ##STR123##

The subtitle compound was prepared by the method of Example 61(b), butstarting with 6-chloro-1,3-benzodioxole-5-carbaldehyde (12.9 g). Yield9.4 g, m.p.: 66-68° C.

¹ H NMR (300 MHz, CDCl₃): δ=3.42 (d, 1H exchangeable), 3.77 (s, 3H),5.48 (d, 1H), 5.98 (s, 2H), 6.82 (s, 1H), 6.83 (s, 1H). LRMS(Thermospray): 262 (MNH₄ ⁺).

(b) Methyl 2-bromo-2-(6-chloro-1,3-benzodioxol-5-yl)acetate ##STR124##

Thionyl bromide (3.7 ml) was added to a stirred solution of methyl2-(6-chloro-1,3-benzodioxol-5-yl)-2-hydroxyacetate from step (a) (7.8 g,32 mmol) in toluene (50 ml) at ambient temperature. After 6 hours thereaction mixture was evaporated in vacuo, and the residue was flashchromatographed using dichloromethane as eluant, followed bycrystallisation from diisopropylether to give the subtitle compound (7.6g).

¹ H NMR (300 MHz, CDCl₃): δ=3.80 (s, 3H), 5.87 (s, 1H), 6.00 (d, 2H),6.80 (s, 1H), 7.26 (s, 1H).

(c) Methyl2-(6-bromo-1H-3-indolyl)-2-(6-chloro-1,3-benzodioxol-5-yl)acetate

The subtitle compound was prepared following the procedure of Example92(c), using methyl 2-bromo-2-(6-chloro-1,3-benzodioxol-5-yl)acetatefrom step (b), m.p. 172-174° C. from diethyl ether and hexane.

¹ H NMR (300 MHz, CDCl₃): δ=3.72 (s, 3H), 5.58 (d, 1H), 5.86 (d, 2H),6.70 (s, 1H), 6.83 (s, 1H), 7.10-7.30 (m, 3H), 7.50 (s, 1H), 8.10 (br,1H). LRMS (Thermospray): 441.2 (MH⁻).

(d) Methyl2-(6-bromo-1-methyl-1H-3-indolyl)-2-(6-chloro-1,3-benzodioxol-5-yl)acetate

The subtitle compound was prepared following the procedure of Example92(d), using methyl2-(6-bromo-1H-3-indolyl)-2-(6-chloro-1,3-benzodioxol-5-yl)acetate fromstep (c), m.p. 183-185° C., from diisopropyl ether.

¹ H NMR (300 MHz, CDCl₃): δ=3.75 (s, 3H), 3.76 (s, 3H), 5.60 (s, 1H),5.90 (d, 2H), 6.77 (s, 1H), 6.87 (s, 1H), 7.06 (s, 1H), 7.17 (d, 1H),7.30 (d, 1H), 7.45 (s, 1H). LRMS (Thermospray): 437.9 (MH⁻).

(e)6-Bromo-3-{1-(6-chloro-1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-indole##STR125##

The subtitle compound was prepared from the compound of step (d)following the methods of Examples 68(c) and 79, and using theappropriate sulphonamide in the last step.

¹ H NMR (300 MHz, CDCl₃): δ=2.46 (s, 3H), 3.71 (s, 3H), 5.36 (s, 1H),5.90 (s, 2H), 6.48 (s, 1H), 6.82 (s, 1H), 6.85 (s, 1H), 7.00 (d, 1H),7.07 (d, 1H), 7.28 (d. 2H), 7.45 (s, 1H), 7.82 (d, 2H), 8.25 (s, 1Hexchangeable). LRMS (APCI): 575.0 (MH⁻).

Example 943-{1-(1,3-Benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-6-formyl-1-methyl-1H-indole##STR126##

Carbon monoxide was bubbled through a stirred solution of3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole(from Example 55, 400 mg, 0.79 mmol), sodium formate (107 mg, 1.57 mmol)and dichlorobis(triphenylphosphine)-palladium (II) (11 mg, 0.016 mmol)in dimethylformamide (6 ml) at 110° C. for 4 h. The reaction mixture wascooled and extracted from 1N hydrochloric acid with ethyl acetate (2×50ml). The organic layers were dried (MgSO₄) and concentrated. Flashcolumn chromatography (elution with 95% dichloromethane/5% methanol)gave the product (320 mg) as a fawn solid.

¹ H NMR (400 MHz, CDCl₃): δ=2.40 (s, 3H), 3.80 (s, 3H), 5.05 (s, 1H),5.90 (s, 2H), 6.60 (m, 3H), 7.05 (s, 1H), 7.2-7.6 (m, 4H), 7.80 (m, 3H),9.20 (brs, 1H), 10.00 (s, 1H). LRMS (Thermospray): 491.4 (MH⁻).

Example 953-{1-(1,3-Benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-6-(hydroxymethyl)-1-methyl-1H-indole##STR127##

Sodium borohydride (51 mg, 1.33 mmol) was added to a stirred solution of3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole(from Example 94, 305 mg, 0.66 mmol) in ethanol (10 ml) at roomtemperature under a nitrogen atmosphere. After 1 h the ethanol wasremoved in vacuo and the product was extracted from 0.5N hydrochloricacid (50 ml) with dichloromethane (2×50 ml). The organic layers weredried (MgSO₄) and concentrated. Flash column chromatography (elutionwith 95% dichloromethane/5% methanol) gave the product (230 mg) as awhite foam.

¹ H NMR (400 MHz, d₆ -DMSO): δ=2.35 (s, 3H), 3.60 (s, 3H), 4.50 (s, 2H),4.95 (brs, 1H), 5.05 (s, 1H), 5.90 (s, 2H), 6.60 (s, 1H), 6.65 (d, 1H),6.70 (d, 2H), 6.80 (d, 1H), 7.00 (d, 1H), 7.20 (s, 1H), 7.35 (d, 2H),7.70 (d, 2H). LRMS (Thermospray): 493.2 (MH⁺). Analysis: Found: C,60.40; H, 5.29; N, 5.79. C₂₆ H₂₄ BrN₂ O₆ S.1.5H₂ O; requires: C, 60.10;H, 5.24; N, 5.39.

Example 966-Formyl-3-{1-(7-methoxy-1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-indole##STR128##

Butylithium (0.8 ml of 2.5M solution in hexane) was added to a stirredsolution of6-bromo-3-{1-(7-methoxy-1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-indole(from Example 92, 400 mg, 0.67 mmol) in anhydrous tetrahydrofuran at-75° C. under a nitrogen atmosphere. After 30 minutes dimethylformamide(0.15 ml) was added to the orange solution, and after a further 30minutes the mixture was allowed to warm at 0° C. before quenching withexcess 1N hydrochloric acid. Ethyl acetate was added and the organiclayer was separated and washed with water. The organic layer was dried(magnesium sulphate), and the solvents removed in vacuo. The residue wasflash chromatographed using 1% methanol in dichloromethane as eluant,and the product was crystallised from dichloromethane and diethyl ethermixture to give the title compound (187 mg).

¹ H NMR (300 MHz, d₆ -DMSO): δ=2.33 (s, 3H), 3.61 (s, 3H), 3.72 (s, 3H),3.80 (s, 3H), 5.20 (s, 1H), 5.94 (s, 2H), 6.42 (s, 1H), 6.50 (s, 1H),6.87 (d, 1H), 6.95 (s, 1H), 7.28 (s, 1H), 7.40 (d, 1H), 7.50 (d, 1H),7.66 (d, 1H), 8.02 (s, 1H), 10.00 (s, 1H), 12.28 (brs, 1H exchangeable).LRMS (APCI): 550.3 (MH⁺). Analysis: Found: C, 61.24; H, 5.17; N, 4.61.C₂₈ H₂₆ N₂ O₈ S: requires: C, 61.08; H, 4.76; N, 5.09. m.p.: 233°C.-dec.

Example 973-{1-(6-Chloro-1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-6-formyl-1-methyl-1H-indole##STR129##

Using6-bromo-3-{1-(6-chloro-1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-indole(from Example 93) the title compound was prepared in a similar way toExample 96.

¹ H NMR (300 MHz, CDCl₃): δ=2.44 (s, 3H), 3.82 (s, 3H), 5.41 (s, 1H),5.90 (d, 2H), 6.48 (s, 1H), 6.83 (s, 1H), 7.16 (s, 1H), 7.20-7.33 (m,3H), 7.50 (d, 1H), 7.82 (s, 1H), 7.85 (d, 2H), 8.40 (brs, 1Hexchangeable), 10.02 (s, 1H). LRMS (APCI): 524.9 (MH⁺).

Example 986-(Hydroxymethyl)-3-{1-(7-methoxy-1,3-benzodioxol-5yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H_indole##STR130##

Sodium borohydride (9 mg) was added to a suspension of6-formyl-3-{1-(7-methoxy-1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-indole(from Example 96, 130 mg, 0.24 mmol) in a mixture of ethanol (3 ml) and1,4-dioxane (3 ml) at ambient temperature. Stirring was continued for1.5 hours, and then water was added dropwise until a solution wasachieved. After carefully acidifying with drops of concentratedhydrochloric acid, the solvents were evaporated in vacuo. The residuewas partitioned between ethyl acetate and water, and the organic layerwas separated and rewashed with water. The organic layer was dried(magnesium sulphate) and the solvents removed in vacuo. The residue wascrystallised from a mixture of methanol and diethyl ether to give thetitle compound (105 mg).

¹ H NMR (300 MHz, d₆ -DMSO): δ=2.35 (s, 3H), 3.60 (s, 3H), 3.68 (s, 3H),3.74 (s, 3H), 4.56 (d, 2H), 5.02 (t, 1H exchangeable), 5.16 (s, 1H),5.92 (s, 2H), 6.39 (s, 1H), 6.48 (s, 1H), 6.82-6.98 (m, 4H), 7.16 (d,1H), 7.30 (s, 1H), 7.66 (d, 1H), 12.20 (s, 1H exchangeable). LRMS(Thermospray): 553.6 (MH⁻). Analysis: Found: C, 60.34; H, 5.43; N, 4.71.C₂₈ H₂₈ N₂ O₈ S: Requires: C, 60.86; H, 5.11; N, 5.07. m.p.: 145-147° C.

Example 993-{1-(6-Chloro-1,3-benzodioxol-5yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-6-(hydroxymethyl)-1-methyl-1H-indole##STR131##

Using3-{1-(6-Chloro-1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-6-formyl-1-methyl-1H-indolefrom Example 97, the title compound was prepared by the method ofExample 98.

¹ H NMR (300 MHz, d₆ -DMSO): δ=2.40 (s, 3H), 3.70 (s, 3H), 4.56 (s, 2H),5.05 (t, 1H exchangeable), 5.42 (s, 1H), 5.92 (s, 1H), 5.96 (s, 1H),6.32 (s, 1H), 6.66 (s, 1H), 6.90 (d, 1H), 7.03 (s, 1H), 7.09 (d, 1H),7.36 (s, 1H), 7.40 (d, 2H), 7.73 (d, 2H), 12.22 (s, 1H exchangeable).LRMS (APCI): 527.3 (MH⁻). (Thermospray)L 544.3 (MNH₄ ⁻). m.p.: 207-209°C.

Example 1003-{1-(1,3-Benzodioxol-5yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-5-(hydroxymethyl)-1-methyl-1H-indole##STR132##

To a solution of3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-5-bromo-1-methyl-1H-indole(from Example 79, 300 mg, 0.53 mmol) in 1,4-dioxane (1.5 ml) under anitrogen atmosphere was added hydroxymethyltributyl-stannane (253 mg,0.79 mmol), followed by tetrakis(triphenylphosphine)palladium(O) (30mg). The mixture was heated to reflux for 8 hours, and then cooled.Sodium hydroxide solution (1M) was added and the mixture boiled todissolve the product. The solution was decanted clear of an insolubletar residue, and washed with diethyl ether. After acidification withconcentrated hydrochloric acid, the aqueous mixture was extracted withethyl acetate. The organic extract was dried (magnesium sulphate) andthe solvents were evaporated in vacuo. The residue was flashchromatographed using 2% methanol in dichloromethane as eluant to givethe title compound (35 mg).

¹ H NMR (300 MHz, d₆ -DMSO): δ=2.35 (s, 3H), 3.58 (s, 3H), 3.68 (s, 3H),4.47 (d, 2H), 4.95 (t, 1H exchangeable), 5.20 (s, 1H), 5.92 (d, 2H),6.65-7.00 (m, 6H), 7.08 (d, 1H), 7.22 (s, 1H), 7.30 (d, 1H), 7.65 (d,1H), 12.40 (s, 1H exchangeable). LRMS (Thermospray): 540.0 (MNH₄ ⁺).

Example 1016-Acetyl-3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-indole##STR133##

A mixture of3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole(from Example 85, 300 mg, 0.53 mmol), ethyl vinyl ether (0.063 ml),palladium(II)acetate (6 mg), tri-o-tolylphosphine (13 mg) andtriethylamine (0.1 ml) in acetonitrile (5 ml) was heated at reflux for18 hours under a nitrogen atmosphere. After cooling, the solvent wasevaporated in vacuo and the residue was stirred with 2N hydrochloricacid (˜6 ml) for 45 minutes. The mixture was twice extracted with ethylacetate, and then washed with water, and brine. The organic layer wasdried (magnesium sulphate) and the solvents were evaporated in vacuo.The residue was flash chromatographed using a gradient elution of amixture of 90% hexane and 10% ethyl acetate, through to 40% hexane and60% ethyl acetate, to give the title compound (80 mg).

¹ H NMR (400 MHz, CDCl₃): δ=2.38 (s, 3H), 2.60 (s, 3H), 3.42 (s, 3H),3.70 (s, 3H), 5.00 (s, 1H), 5.89 (s, 2H), 6.55 (s, 1H), 6.60-6.70 (m,3H), 6.83 (d, 1H), 7.03 (s, 1H), 7.21 (d, 1H), 7.55 (d, 1H), 7.90 (m,2H), 8.80 (s, 1H exchangeable). LRMS (APCI): 534.7 (MH⁻). Analysis:Found: C, 60.20; H, 4.84; N, 4.83. C₂₈ H₂₆ N₂ O₇ S; 0.4 CH₂ Cl₂Requires: C, 60.00; H, 4.75; N, 4.93.

Example 1023-{1-(1,3-Benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-6-(methoxymethyl)-1-methyl-1H-indole##STR134##

To a solution of3-{1-(1,3-benzodioxol-5yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole(from Example 85, 300 mg, 0.53 mmol) in 1,4-dioxane (1.5 ml) under anitrogen atmosphere was added methoxymethyltributyl-stannane (220 mg,0.66 mmol), followed by tetrakis(triphenylphosphine)palladium(O) (35mg). The mixture was heated to reflux for 16 hours, and then cooled. Anadditional portion of tetrakis(triphenylphosphine)palladium(O) (30 mg)was added, and reflux was continued for a further 8 hours. The solventwas removed in vacuo, and the residue was flash chromatographed using agradient elution of a mixture of 1% methanol and 99% dichloromethane,through to 5% methanol and 95% dichloromethane, to give the titlecompound (33 mg).

¹ H NMR (400 MHz, CDCl₃) δ=2.37 (s, 3H), 3.38 (s, 3H), 3.40 (s, 3H),3.65 (s, 3H), 4.53 (s, 2H), 4.99 (s, 1H), 5.88 (s, 2H), 6.57 (s, 1H),6.62-6.71 (m, 3H), 6.83 (s, 1H), 6.84 (d, 1H), 6.92 (d, 1H), 7.15 (d,1H), 7.25 (s, 1H), 7.90 (d, 1H), 8.77 (s, 1H exchangeable). LRMS (APCI):536.9 (MH⁺).

Example 103N6-Methoxy-N6,1-dimethyl-3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methoxyphenyl)sulfonamido]-2-oxoethyl}-1H-6-indolecarboxamide##STR135##

6-Bromo-1-methylindole was treated according to the method of Example65(a), but using (4-methylphenyl)sulphonamide in place of thesulphonamide of Preparation 11, to give the methyl ester, which was thentreated by the method of Example 4 to give the corresponding acid, whichwas then converted to the title compound by the method of Example 5using (CH₃ O)CH₃ NH.

¹ H NMR (400 MHz, CDCl₃): δ=2.47 (s, 3H), 3.42 (s, 3H), 3.59 (s, 3H),3.75 (s, 3H), 4.98 (s, 1H), 5.93 (s, 2H), 6.65-6.77 (m, 3H), 6.89 (s,1H), 7.02 (d, 1H), 7.22-7.34 (m, 3H), 7.72 (s, 1H), 7.82 (d, 2H), 8.55(brs, 1H exchangeable). Analysis: Found: C, 59.14; H, 4.84; N, 7.35. C₂₈H₂₇ N₂ O₇ S; 0.6 CH₂ Cl₂ : Requires: C, 59.11; H, 4.84; N, 7.31.

Example 1046-Acetyl-3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-indole##STR136##

Methylmagnesium bromide (0.23 ml of a 3M solution in diethyl ether) wasadded dropwise to a stirred solution ofN6-methoxy-N6,1-dimethyl-3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1H-6-indolecarboxamide(from Example 103, 174 mg, 0.32 mmol) in anhydrous tetrahydrofuran (5ml) at -70° C. under a nitrogen atmosphere. The mixture was stirred at-70° C. for an additional 2 hours before warming to room temperature.Aqueous hydrochloric acid (5 ml of 1M solution) was slowly added to themixture, and then it was extracted with ethyl acetate (100 ml). Theorganic phase was separated and washed with brine, dried (magnesiumsulphate) and the solvent were removed in vacuo. The residue was flashchromatographed using a gradient elution of a mixture of 90% hexane and10% ethyl acetate, through to 100% ethyl acetate, to give the titlecompound (18 mg).

¹ H NMR (400 MHz, d₆ -DMSO): δ=2.30 (s, 3H), 2.56 (s, 3H), 3.73 (s, 3H),4.90 (s, 1H), 5.87 (d, 2H), 6.65-6.77 (m, 3H), 7.12 (s, 1H), 7.17-7.23(m, 3H), 7.44 (d, 1H), 7.60 (d, 2H), 7.97 (s, 1H), 12.40 (brs, 1Hexchangeable). LRMS (Thermospray): 506.0 (MH⁻), 522.6 (MNH₄ ⁺).

Example 1053-{1-(1,3-Benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-6-(2-pyridylcarbonyl)-1H-indole##STR137##

n-Butyllithium (0.32 ml of 2.5M solution in hexane) was added to astirred solution of 2-bromopyridine (0.08 ml, 0.8 mmol) in anhydroustetrahydrofuran (5 ml) at -70° C. under a nitrogen atmosphere. After 30minutes a solution ofN6-methoxy-N6,1-dimethyl-3-{1-(1,3-benzodioxol-5yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1H-6-indolecarboxamide(the compound of Example 103, 200 mg, 0.36 mmol) in anhydroustetrahydrofuran (2 ml) was added to the mixture at -70° C. The mixturewas stirred at -70° C. for an additional 4 hours before being warmed to0° C. and then quenched with the addition of water (5 ml). The mixturewas acidified with acetic acid, and extracted with ethyl acetate (100ml). The organic phase was separated and washed with brine, dried(magnesium sulphate) and the solvent was removed in vacuo. The residuewas flash chromatographed using a gradient elution of a mixture of 90%hexane and 10% ethyl acetate, through to 100% ethyl acetate, to give thetitle compound (42 mg).

¹ H NMR (400 MHz, CDCl₃): δ=2.42 (s, 3H), 3.73 (s, 3H), 4.98 (s, 1H),5.91 (s, 2H), 6.60-6.70 (m, 3H), 6.98 (s, 1H), 7.10 (d, 1H), 7.27 (d,2H), 7.48 (dd, 1H), 7.62 (d, 1H), 7.81 (d, 2H), 7.90 (dd, 1H), 8.00 (d,1H), 8.10 (s, 1H), 8.72 (d, 1H). LRMS (APCI): 568.3 (MH⁺).

Example 1063-{1-(1,3-Benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-6-[2-(2-pyridyl)acetyl]-1H-indole##STR138##

Lithium diisopropylamide mono(tetrahydrofuran) (0.53 ml of 1.5M solutionin cyclohexane) was added to a stirred solution of 2-methylpyridine(0.08 ml, 0.8 mmol) in anhydrous tetrahydrofuran (3 ml) at -70° C. undera nitrogen atmosphere. After 20 minutes a solution ofN6-methoxy-N6,1-dimethyl-3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1H-6-indolecarboxamide(the compound of Example 103, 200 mg, 0.36 mmol) in anhydroustetrahydrofuran (2 ml) was added to the mixture at -70° C. The mixturewas stirred at -70° C. for an additional 2 hours before being warmed to0° C. and then quenched with the addition of water (5 ml). The mixturewas acidified with acetic acid, and extracted with ethyl acetate (100ml). The organic phase was separated and washed with brine, dried(magnesium sulphate) and the solvent was removed in vacuo. The residuewas flash chromatographed using a gradient elution of a mixture of 90%hexane and 10% ethyl acetate, through to 100% ethyl acetate, to give thetitle compound (95 mg).

¹ H NMR (400 MHz, d₆ -DMSO): Complex due to keto and enol forms of the(2-pyridyl)acetyl group of the compound.

¹ H NMR (300 MHz, TFA-d): δ=2.43 (s, 3H), 3.79 (s, 3H), 5.21 (s, 1H),5.90 (s, 2H), 6.62 (s, 1H), 6.66 (d, 1H), 6.75 (d, 1H), 7.02 (s, 1H),7.30-7.40 (m, 3H), 7.70 (d, 1H), 7.81 (d, 2H), 7.96-8.08 (m, 2H), 8.13(s, 1H), 8.59 (dd, 1H), 8.78 (d, 1H), 11.5 (exchanged NH, and the CH₂ of(2-pyridyl)acetyl group). LRMS (APCI): 582.7 (MH⁺).

Example 1071-Allyl-3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1H-6-indolecarboxamide##STR139##

The title compound was prepared from 6-bromo-1-ethylindole using themethods of Examples 1(a) (but using allyl bromide in place of ethylbromide), 1(b), 1(d), 2, 3 (but using (4-methylphenyl)sulphonamide), 4and 12.

¹ H NMR (300 MHz, CD₃ OD): δ=2.40 (s, 3H), 4.65 (d, 2H), 4.95 (d, 1H),5.00 (s, 1H), 5.10 (d, 1H), 5.80 (d, 2H), 5.95 (m, 1H), 6.70 (m, 3H),6.95 (s, 1H), 7.10 (s, 1H), 7.20 (d, 2H), 7.40 (d, 1H), 7.70 (d, 2H),7.80 (s, 1H). LRMS (Thermospray): 549.3 (MNH₄ ⁻).

Example 1083-{1-(1,3-Benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1-(2-hydroxyethyl)-1H-6-indolecarboxamide##STR140##

Osmium tetroxide (239 mg, 0.94 mmol), pyridine (0.225 ml, 4.7 mmol) andN-methylmorpholine N-oxide (549 mg, 2.84 mmol) were added to a stirredsolution of1-allyl-3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1H-6-indolecarboxamide(the compound of Example 107), in aqueous tetrahydrofuran (10 mltetrahydrofuran:1 ml H₂ O) at room temperature. After 4 h a solution ofsodium thiosulphate (10 ml) was added and stirring continued for 1 h.The black precipitate was removed by filtration through celite and thesolvent removed in vacuo. The crude diol was redissolved in ethylacetate (50 ml) and washed with 1M hydrochloric acid (50 ml) then brine(50 ml). The organic layer was dried (MgSO₄) and concentrated to give abrown solid. Sodium metaperiodate (1.0 g, 4.7 mmol) dissolved in water(1 ml) was added to a stirred slurry of the brown solid in ethyl acetate(10 ml). After 2 h the mixture was filtered, diluted with ethyl acetate(50 ml) and washed with saturated sodium chloride solution. The organiclayer was dried (magnesium sulphate) and concentrated in vacuo Partialpurification was undertaken at this stage by flash columnchromatography, (elution with 90% dichloromethane/10% methanol) givingan aldehyde intermediate as a fawn solid. Without further purificationthis solid was dissolved in methanol (15 ml) at room temperature under anitrogen atmosphere. Sodium borohydride (36 mg) was added portionwiseover 10 minutes and stirring was continued for 4 h. The methanol wasremoved in vacuo and the residue redissolved in ethyl acetate (50 ml).The ethyl acetate solution was washed with saturated aqueous NH₄ Cl (50ml), dried (MgSO₄) and concentrated to give a yellow foam. Flash columnchromatography (elution with 90% dichloromethane/10% methanol) gave theproduct as a fawn solid (126 mg).

¹ H NMR (300 MHz, d₆ -DMSO): δ=2.40 (s, 3H), 3.60 (m, 2H), 4.10 (m, 2H),5.10 (s, 1H), 5.90 (s, 1H), 6.65 (s, 1H), 6.70 (d, 1H), 6.80 (d, 1H),7.10 (s, 1H), 7.15 (d, 1H), 7.30 (d, 2H), 7.40 (d, 1H), 7.70 (d, 2H),8.00 (s, 1H). LRMS (APCI): 536.2 (MH⁻).

Example 1093-{1-(1,3-benzodioxol-5-yl)-2-[(4-methyl-2-methoxyphenyl)sulfonamido]-2-oxoethyl}-1-(2-methoxyethyl)-1H-6-indolecarboxamide##STR141##

The title compound was prepared from the compound of Example 28(b) usingthe methods of Examples 28(c) (but using CH₃ OCH₂ CH₂ Br in place ofmethyl iodide), 28(d), 28(e), 28(f) and 28(g) (but using thesulphonamide of Preparation 11 in place of p-toluenesulphonamide).

¹ H NMR (300 MHz, d₆ -DMSO): δ=2.35 (s, 3H), 3.20 (s, 3H), 3.60 (m, 2H),3.65 (s, 3H), 4.20 (m, 2H), 5.20 (s, 1H), 5.95 (s, 2H), 6.70 (s, 1H),6.75 (d, 1H), 6.80 (d, 1H), 6.85 (d, 1H), 6.90 (s, 1H), 7.15 (s, 1H),7.20 (d, 1H), 7.45 (d, 1H), 7.60 (d, 1H), 7.80 (brs, 1H), 8.00 (s, 1H).LRMS (Thermospray): 580.8 (MH⁺).

Example 110

The compounds of Examples 17, 50, 65, 83, 101 and 109 were tested inTest A above, and found to have an IC₅₀ (ET_(A))<500 nM, and aselectivity for ET_(A) receptors over ET_(B) receptors of greater than100.

The preparation of some aromatic sulphonamides is described below.

Preparation 1 2-Ethyl-4-methyl-1-benzenesulfonamide ##STR142##

n-Butyllithium (5.3 ml of 2.5M in hexane solution) was added to astirred solution of N1-(tert-butyl)-2-ethyl-4-methyl-1-benzensulfonamide(1 g, 4.45 mmol) in tetrahydrofuran (30 ml) at 0° C. under a nitrogenatmosphere. After 2 h bromoethane was added dropwise. After 4 h thereaction mixture was poured into aqueous ammonium chloride and theproduct was extracted with ethyl acetate (2×100 ml). The combinedorganic fractions were washed with brine (100 ml), dried (MgSO₄) andconcentrated in vacuo. A mixture of ethyl acetate (8 ml) and hexane (2ml) was added and a white solid crystallised (450 mg).

¹ H NMR (400 MHz, CDCl₃): δ=1.20 (s, 9H), 1.30 (t, 3H), 2.40 (s, 3H),3.00 (q, 2H), 4.40 (s, 1H), 7.00 (d, 1H), 7.10 (s, 1H), 7.80 (d, 1H).LRMS (Thermospray): 256.4 (MH⁺).

Polyphosphoric acid (approx. 10 ml) was added to this white solid andthe slurry was heated at 100° C. for 30 mins. The yellow solution wasthen carefully poured into iced water (100 ml) and extracted with ethylacetate (2×100 ml). The organic layers were dried (MgSO₄) andconcentrated. The product was purified by flash column chromatography(gradient elution from dichloromethane to 5% methanol/dichloromethane)giving the desired sulphonamide as a white solid.

¹ H NMR (400 MHz, CDCl₃): δ=1.30 (t, 3H), 2.40 (s, 3H), 3.00 (q, 2H),4.80 (brs, 2H), 7.05 (d, 1H), 7.20 (s, 1H), 7.80 (d, 1H). LRMS(Thermospray): 216.5 (MNH₄ ⁺).

Preparation 2 2-Fluoro-4-methyl-1-benzenesulfonamide ##STR143##

2-Fluoro-4-methylaniline (3 g, 24 mmol) was dissolved in glacial aceticacid (45 ml) and concentrated hydrochloric acid (15 ml) and the solutionwas cooled to -10° C. with overhead stirring. Sodium nitrite (1.82 g,26.4 mmol) in water (3 ml) was added dropwise over 0.5 h maintaining thetemperature below -5° C. Stirring was continued for a further 0.5 hafter the final addition. This mixture was added in small portions to astirred, saturated solution of sulphur dioxide in acetic acid (30 ml) at0° C. After addition the mixture was warmed to room temperature andstirred 1 h before pouring into iced water. After stirring for 0.5 h theproduct was extracted into ether and the aqueous layer further extractedwith dichloromethane. The organic layers were combined, washed withbrine, dried (MgSO₄) and concentrated (azeotroping with toluene toremove any remaining acetic acid). A mixture of 1,4-dioxan (30 ml) andaqueous ammonia (30 ml of 0.88M) was added to the residue which wasstirred overnight. The 1,4-dioxan was removed in vacuo and the aqueouslayer extracted with ethyl acetate (2×100 ml). The organic layers werecombined, washed with brine (100 ml), dried (MgSO₄) and concentrated.Flash column chromatography (elution with 99% dichloromethane/1%methanol) gave the product as a pale yellow solid (1.62 g).

¹ H NMR (400 MHz, CDCl₃): δ=1.30 (t, 3H), 2.40 (s, 3H), 3.00 (q, 2H),4.80 (brs, 2H), 7.05 (d, 1H), 7.20 (s, 1H), 7.80 (d, 1H). LRMS (APCI):216.5 (MNH₄ ⁺).

Preparation 3 Ethyl (E)-3-(4-sulfamoylphenyl)-2-propenoate ##STR144##

The title compound was prepared by the method of Example 57 from thestarting material shown.

¹ H NMR (400 MHz, CD₃ OD): δ=1.40 (t, 3H), 4.25 (q, 2H), 6.60 (d, 1H),7.70 (d, 1H), 7.75 (d, 2H), 7.90 (d, 2H). LRMS (Thermospray): 272.9(MNH₄ ⁻).

Preparation 4 5-Methyl-2-pyridinesulfonamide ##STR145##

Sec-butyllithium (9.8 ml of 1.3M in cyclohexane) andN,N,N',N'-tetramethylethylenediamine (1.8 ml, 12.2 mmol) were added to astirred solution of 2-bromo-5-methylpyridine (2 g, 11.6 mmol) at -78° C.under a nitrogen atmosphere. After 90 min sulphur dioxide (approximately30 ml) was condensed into the reaction mixture using a cold finger andthe reaction mixture was slowly warmed to room temperature over 12 h.The reaction mixture was concentrated to dryness and the residuedissolved in ice-water. To this was added a mixture of sodium hydroxide(1.39 g, 35 mmol) and hydroxylamine sulphonic acid (3.9 g, 35 mmol) inwater (20 ml). After 24 h the solution was extracted with ethyl acetate,dried (MgSO₄) and concentrated. Flash column chromatography (95%dichloromethane/5% methanol) gave the product (250 mg) as a clear oilwhich crystallised on standing.

¹ H NMR (400 MHz, CDCl₃): δ=2.40 (s, 3H), 5.20 (brs, 2H), 7.80 (d, 1H),7.90 (d, 1H), 8.50 (s, 1H). LRMS (Thermospray): 172.8 (MH⁺).

Preparation 5 6-(Dimethylamino)-3-pyridinesulfonamide ##STR146##

Chlorosulphonamide (500 mg) was dissolved in ethanol (5 ml) anddimethylamine (15 ml of a 2M solution in tetrahydrofuran). The reactionmixture was sealed in a pressure bomb and heated at 100° C. for 12 h.The mixture was cooled and the solvent removed in vacuo. Flash columnchromatography (elution with 95% dichloromethane/5% methanol) gave theproduct (550 mg) as a pale orange solid.

¹ H NMR (400 MHz, CDCl₃): δ=3.20 (s, 6H), 4.80 (brs, 2H), 6.50 (d, 1H),7.80 (d, 1H), 8.65 (s, 1H). LRMS (Thermospray): 202.2 (MH⁻).

Preparation 6 5-Chloro-2-ethoxy-4-methoxy-1-benzenesulfonamide

(a) 1-Chloro-4-ethoxy-2-methylbenzene ##STR147##

To a solution of 1-chloro-4-hydroxymethylbenzene (14.2 g, 0.1 mol) intetrahydrofuran (250 ml) was added sodium hydride as a 40% suspension inoil (4 g, 0.1 mol) portionwise under a nitrogen. When effervescenceceased iodoethane (15.6 g, 0.1 mol) was added and the solution heated atreflux for 8 hours. The reaction was quenched with water and extractedwith ethyl acetate. The organic layer was washed with dilute aqueoussodium hydroxide and brine, then dried (MgSO₄) and evaporated todryness. The subtitle compound was obtained as a clear oil (17.3 g).

¹ H NMR (300 MHz, CDCl₃): δ=1.40 (t, 3H), 2.35 (s, 3H), 4.00 (q, 2H),6.65 (dt, 1H), 6.75 (d, 1H), 7.20 (d, 1H).

(b) 5-Chloro-2-ethoxy-4-methyl-1-benzenesulfonamide ##STR148##

To 1-chloro-4-ethoxy-2-methylbenzene (from step (a), 17 g) was addedchlorosulphonic acid (25 ml) dropwise with stirring and ice cooling. Thesolution was stirred for 30 minutes then poured onto ice (200 ml) andthe crude intermediate sulphonyl chloride filtered off. This materialwas mixed thoroughly with ammonium carbonate solid (35 g) and heated at100° C. for 30 minutes. The mixture was cooled and poured onto ice waterthen filtered off and crystallised from hot ethyl acetate (15.2 g), m.p.153-5° C.

¹ H NMR (300 MHz, d₆ -DMSO): δ=1.40 (t, 3H), 2.40 (s, 3H), 4.20 (q, 2H),7.00 (s, 2H), 7.25 (s, 1H), 7.60 (s, 1H). LRMS (Thermospray): 267.5(MNH₄ ⁺).

Preparation 7 5-Chloro-2-(2-methoxyethoxy)-4-methyl-1-benzenesulfonamide

(a) 1-Chloro-4-(2-methoxyethoxy)-2-methylbenzene ##STR149##

The subtitle compound was prepared using the method of Preparation 6(a),but using CH₃ OCH₂ CH₂ Br in place of iodoethane.

¹ H NMR (300 MHz, CDCl₃): δ=2.35 (s, 3H), 3.45 (s, 3H), 3.75 (t, 2H),4.05 (t, 2H), 6.70 (dd, 1H), 6.80 (d, 1H), 7.20 (d, 1H).

(b) 5-Chloro-2-(2-methoxyethoxy)-4-methyl-1-benzenesulfonamide##STR150##

The title compound was prepared from the product of step (a) by themethod of Preparation 6(b).

¹ H NMR (300 MHz, CDCl₃): δ=2.40 (s, 3H), 3.45 (s, 3H), 3.80 (t, 2H),4.25 (t, 2H), 5.45 (s, 2H), 6.85 (s, 1H), 7.90 (s, 1H). LRMS(Thermospray): 297.1 (MNH₄ ⁻).

Preparation 8 5-Chloro-2-methoxy-4-methyl-1-benzenesulfonamide##STR151##

The title compound was prepared by the method of Preparation 6, butusing iodomethane in place of iodoethane.

¹ H NMR (300 MHz, CDCl₃): δ=2.40 (s, 3H), 4.00 (s, 3H), 5.00 (s, 2H),6.90 (s, 1H), 7.85 (s, 1H). LRMS (Thermospray): 252.9 (MNH₄ ⁺).

Preparation 9 2-Ethoxy-4-methyl-1-benzenesulfonamide ##STR152##

To a solution of the chlorosulphonamide from Preparation 6 (5.0 g) inethanol (25 ml) and water (25 ml) was added Raney nickel (4 g of a 50%suspension in water) and the mixture heated at reflux for 24 hours. Hotmethanol (100 ml) was added and the reducing agent removed byfiltration. Solvents were evaporated and the residue crystallised fromhot ethanol (2.42 g), m.p. 136-7° C.

¹ H NMR (300 MHz, d₆ -DMSO): δ=1.40 (t, 3H), 2.35 (s, 3H), 4.20 (q, 2H),6.75 (s, 2H), 6.80 (d, 1H), 7.00 (s, 1H), 7.60 (d, 1H). LRMS(Thermospray): 233.5 (MNH₄ ⁺).

Preparation 10 2-(2-Methoxyethoxy)-4-methyl-1-benzenesulfonamide##STR153##

The title compound was prepared by the method of Preparation 9 from theproduct of Preparation 7.

¹ H NMR (300 MHz, CDCl₃): δ=2.40 (s, 3H), 3.45 (s, 3H), 3.80 (t, 2H),4.25 (t, 2H), 5.20 (s, 2H), 6.80 (s, 1H), 6.90 (d, 1H), 7.80 (d, 1H).LRMS (Thermospray): 246 (MH⁺).

Preparation 11 2-Methoxy-4-methyl-1-benzenesulfonamide ##STR154##

The title compound was prepared by the method of Preparation 9 from theproduct of Preparation 8.

¹ H NMR (300 MHz, CDCl₃): δ=2.40 (s, 3H), 4.00 (s, 3H), 5.00 (brs, 2H),6.80 (m, 2H), 7.80 (d, 1H). LRMS (Thermospray): 219.0 (MNH₄ ⁺).

What is claimed is:
 1. A compound of formula I, ##STR155## wherein R¹ and R² are optional substituents and independently represent C₁₋₆ alkyl, C₂₋₆ alkenyl (optionally substituted by CO₂ H or CO₂ (C₁₋₆ alkyl), C₂₋₆ alkynyl, halogen, C₁₋₃ perfluoroalkyl, (CH₂)_(m) Ar¹, (CH₂)_(m) Het¹, (CH₂)_(m) CONR⁷ R⁸, (CH₂)_(m) CO₂ R⁸, O(CH₂)_(q) CO₂ R⁸, (CH₂)_(m) COR⁸, (CH₂)_(m) OR⁸, O(CH₂)_(p) OR⁸, (CH₂)_(m) NR⁷ R⁸, CO₂ (CH₂)_(q) NR⁷ R⁸, (CH₂)_(m) CN, S(O)_(n) R⁸, SO₂ NR⁷ R⁸, CONH(CH₂)_(m) Ar¹ or CONH(CH₂)_(m) Het¹ ;R³ represents H, C₁₋₆ alkyl, (CH₂)_(p) NR⁹ R¹⁰, SO₂, R¹⁰, SO₂ NR⁹ R¹⁰, (CH₂)_(m) COR¹⁰, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CH₂)_(m) CONR⁹ R¹⁰, (CH₂)_(m) CO₂ R¹⁰, (CH₂)_(p) CN, (CH₂)_(p) R¹⁰ or (CH₂)_(p) OR¹⁰ ; R⁴ and R⁹ independently represent H or C₁₋₆ alkyl; R⁷ represents H, C₁₋₆ alkyl or C₁₋₆ alkoxy; R⁵ represents H or OH; R⁸ and R¹⁰ independently represent H, C₁₋₆ alkyl, Ar², Het² or C₁₋₆ alkyl substituted by Ar² or Het² ; Z represents CO₂ H, CONH(tetrazol-5-yl), CONHSO₂ O(C₁₋₄ alkyl), CO₂ Ar³, CO₂ (C₁₋₆ alkyl), tetrazol-5-yl, CONHSO₂ Ar³, CONHSO₂ (CH₂)_(q) Ar³ or CONHSO₂ (C₁₋₆ alkyl); m represents 0, 1, 2 or 3; n represents 0, 1 or 2; p represents 2, 3 or 4; q represents 1, 2 or 3; Ar¹⁻³ independently represent phenyl, naphthyl, or an aromatic heterocycle having 6 ring members one of which is selected from N, S and ), which aromatic heterocycle is optionally fused to a benzene ring, and which phenyl group is optionally fused to an aromatic heterocycle as defined immediately above, the group as a whole being optionally substituted by one or more groups falling within the definition of R¹ above; and Het¹ and Het² independently represent a non-aromatic heterocycle having 6 ring members one of which is selected from N, S and O, which group is optionally substituted by one or more groups falling within the definition of R¹ above, and is further optionally substituted by ═O or ═S; or a pharmaceutically acceptable salt thereof.
 2. A compound as claimed in claim 1, wherein R¹ represents halogen, (CH₂)_(m) CONR⁷ R⁸, (CH₂)_(m) CO₂ R⁸, (CH₂)_(m) COR⁸, (CH₂)_(m) OR⁸ or (CH₂)_(m) CN.
 3. A compound as claimed in claim 1, wherein R² is absent.
 4. A compound as claimed in claim 1, wherein R³ represents H, C₁₋₆ alkyl, or (CH₂)_(p) OR¹⁰.
 5. A compound as claimed in claim 1, wherein R⁴ represents H.
 6. A compound as claimed in claim 1, wherein R⁵ represents H.
 7. A compound as claimed in claim 1, wherein R⁶ represents methylenedioxyphenyl.
 8. A compound as claimed in claim 1, wherein Z represents CO₂ H or CONHSO₂ Ar³.
 9. A pharmaceutical formulation comprising a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
 10. A method of treatment of restenosis, renal failure, pulmonary hypertension, benign prostatic hypertrophy, congestive heart failure, stroke, angina, atherosclerosis, cerebral and cardiac ischaemia or cyclosporin induced nephrotoxicity, which comprises administering a therapeutically effective amount of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment.
 11. A process for the production of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, which comprises:(a) when R⁵ represents H, reaction of a compound of formula IIA, ##STR156## wherein R¹⁻⁴ are as defined in claim 1, with a compound of formula III, ##STR157## wherein R⁶ and Z are as defined in claim 1, in the presence of a Lewis acid or trifluoroacetic acid, and a tri(C₁₋₆ alkyl)silane; (b) when R⁵ represents OH, reaction of a compound of formula IIA, as defined above, with a compound of formula III, as defined above, in the presence of a Lewis acid; (c) when R³ represents H and R⁵ represents H, treatment of a compound of formula IIB, ##STR158## wherein R¹, R² and R⁴ are as defined in claim 1, with a Grignard reagent, followed by reaction with a compound of formula III, as defined above, followed by treatment with a Lewis acid or trifluoroacetic acid, and a tri(C₁₋₆ alkyl)silane; (d) when R³ represents H and R⁵ represents H, treatment of a compound of formula IIB, as defined above, with a Grignard reagent, followed by reaction with a compound of formula IV, ##STR159## wherein R⁶ and Z are as defined in claim 1, and Hal represents halogen; (e) when R⁵ represents H, reaction of a compound of formula IIA, as defined above, with a compound of formula IV, as defined above, in the presence of a hindered, non-nucleophilic base; (f) reacting a compound of formula I, in which R¹ represents Br, with CO gas in the presence of a palladium catalyst and a reducing agent, to provide the corresponding compound of formula I in which R¹ represents CHO; (g) reacting a compound of formula I, in which R¹ represents Br, with CO gas in the presence of a palladium catalyst and a C₁₋₆ alkanol, to provide the corresponding compound of formula I in which R¹ represents CO₂ (C₁₋₆ alkyl); (h) coupling a compound of formula I, in which Z represents CO₂ H, with a compound of formula VI,

    H.sub.2 NSO.sub.2 Ar.sup.3                                 VI

wherein Ar³ is as defined in claim 1, to provide the corresponding compound of formula I in which Z represents CONHSO₂ Ar³ ; or (i) reacting a compound of formula I, in which R¹ represents Br, with an alkyl lithium reagent and quenching with dimethylformamide or carbon dioxide to give a corresponding compound in which R¹ represents CHO or CO₂ H respectively; and where desired or necessary converting the resulting compound of formula I into a pharmaceutically acceptable salt thereof or vice versa. 